The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index; 7 of the 15 sources its claims cite were checked for support.
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition
Open accessAbstract
Histone deacetylase 6 (HDAC6) is a critical target for drug design because of its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens HDAC6 and of CD1 and CD2 from Danio rerio HDAC6. We correlated these structures with activity measurements using 13 different substrates. The catalytic activity of CD2 from both species exhibited broad substrate specificity, whereas that of CD1 was highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yielded unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with eight different inhibitors, including belinostat and panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2-oxoethyl)benzamide, revealed surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
7 of 15 cited sources checked · 5 supported · 1 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In HDAC8, highly conserved D101 accepts hydrogen bonds from the two backbone amide groups flanking the scissile acetyllysine residue.37,38”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
What the sources say
- Supportedcites [37] Vannini, A. et al. Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep. 8, 879–884 (2007). source
The scientific report states that HDAC8 Asp101’s side-chain carboxylate forms two hydrogen bonds with adjacent nitrogen atoms of the substrate backbone (Fig. 3B). It also describes Asp101 as conserved and identifies the acetylated lysine bound in the active site (Results and Discussion). (LLM, conf=0.88)
- Partly supportedcites [38] Dowling, D.P., Gantt, S.L., Gattis, S.G., Fierke, C.A. & Christianson, D.W. Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry 47, 13554–13563 (2008). sourceExperimental — accuracy not yet measured
The Results and Discussion state that strictly conserved D101 accepts hydrogen bonds from two substrate backbone NH groups. They identify those groups as belonging to the acetyllysine residue itself and the adjacent n+1 residue, rather than two residues flanking the acetyllysine. (LLM, conf=0.84)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“this contrasts with HDAC8, in which the second histidine of the tandem pair serves as a single general base-general acid.33”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
What the sources say
- Supportedcites [33] Gantt, S.M. et al. General base-general acid catalysis in human histone deacetylase 8. Biochemistry 55, 820–832 (2016). source
The Conclusions identify H143, the second histidine in the H142–H143 tandem pair, as a single general base–general acid catalyst in HDAC8. The Discussion likewise concludes that H143 serves as both the general acid and the general base catalyst. (LLM, conf=0.95)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
In the paper
“Consistent with this hypothesis, K330L zCD1 exhibited more relaxed substrate specificity in comparison with wild-type zCD1 (Supplementary Fig. 2).”
- Also stated in: § Basis of CD1 specificity for X-K(Ac)-CO2− substrates · plain
“K330L zCD1 exhibited more relaxed substrate specificity in comparison with wild-type zCD1”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
What the sources say
- Not matchedcites Supplementary Fig. 2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Basis of CD1 specificity for X-K(Ac)-CO2− substrates · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the next snapshot of catalysis – the tetrahedral intermediate – was provided by the 1.80 Å-resolution structure of the complex between substrate 8 (derived from histone H4) and H574A zCD2.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the crystal structure of the resting enzyme showed that the catalytic Zn2+ ion resides at the base of a ~10 Å deep tunnel, liganded by D612, H614, D705, and a water molecule with distorted tetrahedral coordination geometry.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This mutant exhibited compromised activity due to the loss of the catalytically obligatory general acid.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“their active site contours were highly similar.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we prepared Y745F zCD2, which exhibited compromised activity due to the loss of substrate activation by Y745.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the catalytic efficiency was reduced by only 3–4-fold when the least favored substrates 11 and 13 were compared to the optimal substrate 12”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The catalytic activity of CD2 from both species exhibits broad substrate specificity”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 53
- Probably not a substantial claim. 9
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“HC toxin exhibits irreversible inhibition against maize HD1-B (a class I HDAC), but reversible inhibition against HD1-A (a class II HDAC).39”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
What the sources say
- Disputedcites [39] Brosch, G., Ransom, R., Lechner, T., Walton, J.D. & Loidl, P. Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum. Plant Cell 7, 1941–1950 (1995). sourceExperimental — accuracy not yet measured
The Abstract (p. 1941) says HD1-A and HD1-B were similarly inhibited by HC toxin and describes the inhibition as reversible. That contradicts the claimed irreversible inhibition of HD1-B. The passage does not assign either enzyme to an HDAC class. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“trapoxin contains the Aoe moiety and is a potent irreversible inhibitor of HDAC1, but it is a reversible inhibitor of HDAC6.40”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
What the sources say
- Supportedcites [40] Furumai, R. et al. Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc. Natl. Acad. Sci. USA 98, 87–92 (2001). source
The paper identifies Aoe as part of trapoxin’s side chain and describes its epoxyketone group as causing irreversible inhibition of HDAC1. The Results section reports that trapoxin’s inhibition of HDAC6 was reversible after the drug was removed. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The quality of each model was verified with PROCHECK55 and MolProbity.56”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > ONLINE METHODS > Crystal structure determination
What the sources say
- Not checked — no full text of the sourcecites [55] Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993). source
- Supportedcites [56] Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010). source
The citation identifies MolProbity as a tool for validating model quality. The ‘Summary of MolProbity flow and user interactions’ describes its validation analyses and reports, supporting that use. The source need not document the citing authors’ own models. (LLM, conf=0.93)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Accordingly, the potency of HPOB against HDAC6 is comparable to SAHA-like inhibitors, but HPOB potency against other isozymes is significantly reduced.43”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > HDAC6 inhibitor selectivity
What the sources say
- Supportedcites [43] Lee, J.H. et al. Development of a histone deacetylase 6 inhibitor and its biological effects. Proc. Natl. Acad. Sci. USA 110, 15704–15709 (2013). source
In “HPOB Is a Selective Inhibitor of HDAC6” (page unavailable), the paper reports an HPOB IC50 of 0.056 μM for HDAC6 versus at least 1.7 μM for the other HDAC enzymes tested, and describes SAHA as a potent HDAC6 inhibitor. It also states that HPOB selectively inhibits HDAC6 compared with pan-HDAC inhibitors, supporting the cited qualitative comparison. (LLM, conf=0.88)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“hCD1 (Y782F hCD12) exhibited robust catalytic efficiency (~1,000 M−1s−1) compared to hCD2 (Y386F hCD12) with substrates 9 and 10”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“zCD1 was less active than zCD2 (kcat/KM is reduced 21-fold and 7-fold for substrates 1 and 8, respectively).”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The electron density map indicated that the scissile carbonyl of acetyllysine underwent nucleophilic attack by a water molecule activated by H573 and Zn2+ to yield a tetrahedral intermediate, trapped in the active site due to the loss of the general acid H574”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“significant hCD1 activity in Y782F hCD12 was observed with C-terminal acetyllysine peptide substrates 9 and 10, indicating that hCD1 was indeed catalytically active, but exhibited strict substrate specificity for substrates bearing C-terminal acetyllysine residues”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The 1.82 Å-resolution structure of the enzyme-substrate complex revealed that the scissile carbonyl of acetyllysine coordinates to the formerly vacant site on Zn2+ without displacing the Zn2+-bound water molecule, resulting in a pentacoordinate metal ion poised for catalysis”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“both hCD2 and zCD2 exhibited broad substrate specificity.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the zCD2 active site, only N530 and N645 were not conserved, appearing as D567 and M682 in hCD2; moreover, these residues were at the outer rim of the active site and were quite distant from bound inhibitors.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The crystal structure of hCD2 as a fusion construct with maltose binding protein was similar to that of zCD2 (59%/75% sequence identity/similarity) (Supplementary Fig. 5), with an r.m.s. deviation of 0.43 Å for 314 Cα atoms”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“oxyanion atom O1 is stabilized by coordination to Zn2+ (2.1 Å) and a hydrogen bond with Y745; hydroxyl group O2 is somewhat distant from Zn2+ for inner sphere coordination (2.6 Å), but hydrogen bonds with H573.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The hydrolysis of C-terminal acetyllysine substrates by hCD1 required an intact tandem domain assembly, since hCD1 was not catalytically active as an isolated domain.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The individual hCD2 domain was slightly less active (5-fold) than hCD12, whereas no activity was detected with hCD1 at up to 5 μM protein.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“zCD1 was as active as zCD2 with substrates 9 and 10, but less active than zCD2 with substrates 11–13 (20–380-fold reduced kcat/KM).”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“showing that mutation of hCD1 does not significantly affect catalysis, whereas mutation of hCD2 essentially abolished catalytic activity.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We now report the crystal structures of CD2 from Homo sapiens and CD1 and CD2 from Danio rerio HDAC6”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“both catalytic domains of zHDAC6 were active when assayed with fluorogenic substrates, even when assayed as individual domains.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in the full-length human and zebrafish enzymes, CD2 exhibited broad substrate specificity for endo- and exo-acetyllysine peptide substrates X-K(Ac)-X, X-K(Ac)-Pro-X, and X-K(Ac)-CO2−, whereas hCD1 exhibited strict substrate specificity for exo-acetyllysine peptide substrates X-K(Ac)-CO2−; substrate specificity for zCD1 was somewhat more relaxed.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Substrate specificity and activity of HDAC6 CD1 and CD2
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The binding of the gem-diol moiety was comparable to that observed for the binding of the tetrahedral intermediate with substrate 8, making asymmetric metal coordination interactions with Zn2+-O1 and Zn2+-O2 distances of 2.0 Å and 2.5 Å, respectively.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mutations of zCD2 N530 and hCD2 D567 did not significantly affect activity, whereas mutations of hCD2 S568 and zCD2 S531 decreased catalytic efficiency by 10-fold and 258-fold, respectively.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These amino acid substitutions abolished activity with endo-acetyllysine peptide substrate 8 (Fig. 1b) and conferred significant specificity for substrates 9 and 10, which bear an exo-acetyllysine group”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In zCD1, the active site was slightly more constricted, due in part to the protruding side chain of K330, which donates a hydrogen bond to the carbonyl group of the “cap” moiety of TSA and sterically displaces it toward the L1 loop.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observed significant catalytic activity for HDAC6 zCD2, but not HDAC8, using substrates with Lys(Ac)-Pro linkages”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the ketone carbonyl of Aoe was hydrated so that the inhibitor binds as a gem-diol(ate), much like that observed for the trifluoroketone (Supplementary Fig. 6c) or for the tetrahedral intermediate with substrate 8 (Fig. 2c).”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“zCD1 and hCD1 exhibited low or no activity when assayed with traditional fluorogenic substrates 1–8, but instead were very specific for the hydrolysis of exo-acetyllysine substrates 9 and 10, X-K(Ac)-CO2−”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two amino acid substitutions further constrict the active site of hCD1 in addition to K353 (which corresponds to K330 of zCD1): F202 and H82 in zCD1 (Fig. 4a) appear as Y225 and F105 in hCD1.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“O1 formed a hydrogen bond with Y745, and O2 formed a hydrogen bond with H573 and H574.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, the hydroxamate groups of all broad-specificity inhibitors tended toward bidentate Zn2+ coordination (Fig. 5b and Supplementary Table 5), displacing the Zn2+-bound water molecule of the resting enzyme, with the hydroxamate OH and C=O groups additionally interacting with H573 and Y745, respectively.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > HDAC6 inhibitor selectivity
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the L-Ala–D-Ala and the L-Aoe–D-Pro peptide linkages of HC toxin adopted cis configurations, giving the cyclic tetrapeptide unusual alternating cis-trans-cis-trans peptide bond geometry.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the corresponding residue in zCD2, N530, was offset such that S531 of zCD2 structurally aligned with D101 of HDAC8 and accepted a hydrogen bond from the backbone NH group of acetyllysine in substrates 1 and 8”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding residue in zCD2 was L712, which does not protrude as far into the active site.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“substrate binding to zCD2 does not trigger any major conformational changes in the L1 and L2 loops surrounding the active site, so the active site is essentially pre-formed for substrate binding”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The tetrahedral intermediate was also mimicked by the binding of a trifluoroketone inhibitor35 as a tetrahedral gem-diol with Ki = 0.8 μM”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
What the sources say
- Not checked — no full text of the sourcecites [35] Decroos, C., Bowman, C.M. & Christianson, D.W. Synthesis and evaluation of N8-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase. Bioorg. Med. Chem. 21, 4530–4540 (2013). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This residue appeared as P519 in zCD2 and did not trigger a conformational change of the corresponding tryptophan residue, W459.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No major conformational changes of HDAC6 accompanied the binding of HC toxin to zCD2 (Ki = 0.35 μM)”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the Aoe O1 atom coordinates to Zn2+ (2.0 Å) and hydrogen bonds with Y745; the O2 atom makes a weak coordination interaction with Zn2+ (2.5 Å), and hydrogen bonds with H573 and H574.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the hydroxamate group of the HDAC6-selective inhibitor HPOB (Ki = 1.0 nM) coordinated to Zn2+ only through its OH group, and it did not displace the Zn2+-bound water molecule; the Zn2+ ion is pentacoordinate with square pyramidal geometry (Fig. 5c).”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > HDAC6 inhibitor selectivity
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“similar interactions were observed for the binding of the product acetate anion with Zn2+-O1 and Zn2+-O2 distances of 2.2 Å and 2.1 Å, respectively”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The backbone NH group of Aoe donated a hydrogen bond to S531, and water-mediated hydrogen bond networks were observed between the backbone carbonyl of Aoe and H614, and the backbone NH group of HC toxin L-Ala and H463”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Y225F/Y782F hCD12 exhibited nearly 100-fold enhanced activity with endo-acetyllysine fluorogenic substrates when compared to hCD12 Y782F, whereas K353L/Y782F hCD12 exhibited a more modest 10-fold activity enhancement”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CD2 domains of human and zebrafish HDAC6 can accommodate proline at the +1 position relative to the scissile acetyllysine residue, whereas HDAC8 cannot based on the hydrogen bond between D101 and the backbone NH of the +1 residue.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“H573 could serve as a general base to assist Zn2+ in activating the nucleophilic water molecule, so the tandem histidines in the HDAC6 zCD2 active site may serve separate general base-general acid functions.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“HDAC6 catalyzes the deacetylation of K40 in the α-tubulin subunit of the microtubule,24 thereby regulating microtubule dynamics”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > Abstract
What the sources say
- Not checked — no full text of the sourcecites [24] Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Histone deacetylase 6 (HDAC6) is a critical target for drug design due to its role in oncogenic transformation and cancer metastasis”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“HDAC6 inhibition leads to hyperacetylation of α-tubulin and suppression of microtubule dynamics, while overexpression of HDAC6 reduces tubulin acetylation levels and increases cell motility.25”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > Abstract
What the sources say
- Not checked — no full text of the sourcecites [25] Szyk, A. et al. Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase. Cell 157, 1405–1415 (2014). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we hypothesized that K330 is a “gatekeeper” that confers specificity toward C-terminal acetyllysine substrates by hydrogen bonding with the α-carboxylate group of acetyllysine.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Substrate 8 likely remained bound as a metastable tetrahedral intermediate because an enzyme generally favors the binding of a transition state-like structure over the binding of a substrate-like structure”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We hypothesized that the hydroxyl group of Y202 hydrogen bonds with the α-carboxylate group of the acetyllysine substrates to abolish the binding of endo-acetylysine substrates, such that both K330 and Y202 (K353 and Y225 in hCD1) enforce specificity for substrates bearing an exo-acetyllysine group, X-K(Ac)-CO2−”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Basis of CD1 specificity for X-K(Ac)-CO2− substrates
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the substrate carbonyl was sufficiently activated to undergo nucleophilic attack, but the resulting tetrahedral intermediate was locked in place, deep in the active site pocket – it could not collapse without general acid H574 to protonate the leaving amino group.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we hypothesize that the L-Aoe-D-Pro-L-Ala fragment of HC toxin partially mimics a potential substrate site located in a reverse turn, such as X-Lys(Ac)-Pro-X, as well as other proline-containing loop structures or segments containing cis-Lys(Ac)-X linkages.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The stronger interaction of O1 with Zn2+ may indicate ionization to an oxyanion, which would also be inductively stabilized by the adjacent trifluoromethyl group.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Snapshots of the catalytic mechanism
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we suggest that the amide bond following the scissile acetyllysine residue is dispensable for substrate binding to zCD2 and hCD2, since it makes no direct interactions with active site residues.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The backbone amide group following acetyllysine hydrogen bonded only with a water molecule, suggesting that any amino acid – including proline – could be accommodated at this position.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > RESULTS > Structural basis of peptide recognition by CD2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, comparison of different zCD2-inhibitor structures highlights the structural basis for HDAC6-specific inhibitor design, which exploits a previously unobserved Zn2+ coordination mode by the hydroxamate group of HPOB: inhibitor binding does not require displacement of Zn2+-bound water.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The inhibitor binding modes observed in zebrafish CD2 crystals are representative of human HDAC6.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample size.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > ONLINE METHODS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In general, zinc hydrolases activate a substrate carbonyl group for direct nucleophilic attack by a water molecule using Zn2+ coordination and a hydrogen bond interaction to polarize the carbonyl group; the nucleophilic water molecule is activated by Zn2+ coordination and a general base.44,45”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [44] Matthews, B.W. Structural basis of the action of thermolysin and related zinc peptidases. Acc. Chem. Res. 21, 333–340 (1988). source
- Not checked — no full text of the sourcecites [45] Christianson, D.W. & Lipscomb, W.N. Carboxypeptidase A. Acc. Chem. Res. 22, 62–69 (1989). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Assays were performed in triplicate at room temperature.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > ONLINE METHODS > HDAC6 activity assay
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No backbone torsion angles adopt disallowed conformations in any structure.”
§ Histone deacetylase 6 structure and molecular basis of catalysis and inhibition > ONLINE METHODS > Crystal structure determination
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Before this study, no crystal structures of HDAC6 catalytic domains existed.
“Despite these unresolved structure-function relationships, no crystal structures of HDAC6 catalytic domains have been available until now.”
The paper relies on this without support.
The active site of a Zn2+ hydrolase is adapted to allow water to attack almost any carbonyl group and to stabilize the resulting tetrahedral species.
“The active site of a Zn2+ hydrolase has evolved to enable nucleophilic attack of water at virtually any carbonyl group, preferentially stabilizing the resulting tetrahedral species.”
The paper relies on this without support.
The inhibitor binding modes observed in zebrafish CD2 crystals are representative of human HDAC6.
“Finally, comparison of different zCD2-inhibitor structures highlights the structural basis for HDAC6-specific inhibitor design, which exploits a previously unobserved Zn2+ coordination mode by the hydroxamate group of HPOB: inhibitor binding does not require displacement of Zn2+-bound water.”
The paper relies on this without support.
The Aoe side chain carbonyl is isosteric with the scissile carbonyl of acetyllysine.
“Since the carbonyl group of the Aoe side chain is isosteric with the scissile carbonyl of acetyllysine, the binding of Aoe-containing peptides to any HDAC should enable facile hydration of the Aoe ketone carbonyl, as observed in the zCD2-HC toxin complex.”
The paper relies on this without support.
The active site geometry of class I HDACs is sufficiently similar to zCD2 that the nucleophile and inhibitor binding conclusions transfer.
“Presumably, inhibitor binding to class I HDAC active sites allows for a closer contact between the nucleophilic thiol and the electrophilic epoxide to enable covalent bond formation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the recent work on HDAC6/inhibitor complexes demonstrate that L1 loop conformational stability is important for the interactions of L1 loop residues with inhibitors capping groups to achieve HDAC6 selectivity inhibition 42-46”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [42]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Selective inhibition appears to rely on small structural differences between HDAC1-3 and HDAC6 and on small thermodynamic differences in selective inhibitor binding 42-46 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [42]
Experimental — accuracy not yet measuredIn the citing paper
“We recently reported the X-ray crystal structures of both catalytic domains (CDs) of HDAC6, showing that a conserved active site lysine serves as a gatekeeper in CD1, in that it dictates specificity for carboxy-terminal acetyllysine substrates bearing a negatively charged α-carboxylate group17.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
In the citing paper
“In comparison with its closest relative, the cytosolic isozyme HDAC6 (ref. 17), HDAC10 was clearly not an efficient lysine deacetylase.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
In the citing paper
“Interestingly, D94 corresponds to acetyllysine binding residues D101 of hHDAC8 and S568 of hHDAC6 CD2 (refs 17, 30, 31).”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
In the citing paper
“Our enzymological and X-ray crystallographic results suggest that E274 of zHDAC10 is conserved in HDAC10 orthologues as a gatekeeper to establish specificity for a cationic substrate, just as gatekeeper K330 is conserved in the corresponding position of zHDAC6 CD1 to establish specificity for an anionic substrate17.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
In the citing paper
“In zHDAC10, the 310-helix ηA2 provides this steric bulk; in hHDAC6 CD1 (ref. 17), F105 and Y225 provide this steric bulk.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
In the citing paper
“This binding mode was similar to that observed in the APAH–AAT and zHDAC6 CD2–AAT complexes1729.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [17]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Substrate 1 complex is assigned to two different mutants
MinorThe crystallization method identifies the zCD2-substrate 1 complex as Y745F, but the structure-determination section repeatedly identifies it as Y785F. These are different residue numbers for the same reported complex.
“The Y745F zCD2–substrate 1 complex was crystallized using the sitting drop vapor diffusion method at 4 °C”
“Y785F zCD2-substrate 1 complex: 90.6% allowed, 8.7% additionally allowed”
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,882 · cited 1×
“57 The Ramachandran statistics for each model are as follows: zCD1-TSA complex: 90.3% allowed, 9.4% additionally allowed; zCD2-TSA complex: 91.6% allowed, 7.8% additionally allowed; MBP-hCD2-TSA complex: 88.5% allowed, 10.8% additionally allowed; unliganded zCD2: 91.1% allowed, 8.6% additionally…”
Influential[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
PROCHECK: a program to check the stereochemical quality of protein structures
Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889892009944 · Cited by 24,581 · cited 1×
“The quality of each model was verified with PROCHECK 55 and MolProbity.”
PHENIX : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · cited 1×
“51 For the structure of the zCD2–SAHA complex, a model of the HDAC4 catalytic domain in a closed-loop conformation (PDB entry 4CBT) 52 was used as the search probe for rotation and translation function calculations.”
MolProbity : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922
Lysine acetylation targets protein complexes and co-regulates major cellular functions
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V., & Mann, M. (2009) · Science · doi:10.1126/science.1175371 · Cited by 4,040 · cited 1×
“2, 3).”
HDAC6 is a microtubule-associated deacetylase
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.-F., & Yao, T.-P. (2002) · Nature · doi:10.1038/417455a · Cited by 2,403 · cited 1×
“…in the cytoplasm by serine/glutamate-rich repeat motifs, 23 HDAC6 catalyzes the deacetylation of K40 in the α -tubulin subunit of the microtubule, 24 thereby regulating microtubule dynamics: HDAC6 inhibition leads to hyperacetylation of α -tubulin and suppression of microtubule dynamics, while…”
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–300 of 491
Huê, B. T. B., Nguyen, P. H., Quân, P. M., Tran, H. P., Tran, Q. D., Jung, H., Hong, Q. V., Nguyễn, C. Q., Nguyen, Q. P., Le, H. T., et al. (2022) · Molecules · doi:10.3390/molecules27072204 · Cited by 19
Hydrazides as Inhibitors of Histone Deacetylases
Carreiras, M. C., & Marco, J. L. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00541 · Cited by 26
Liu, Y., Li, L., & Min, J. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2158 · Cited by 20
Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6
Xiao, Y., & Zhang, X. (2020) · Future Drug Discovery · doi:10.4155/fdd-2020-0023 · Cited by 20
Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?
Raouf, Y. S., & Moreno–Yruela, C. (2024) · JACS Au · doi:10.1021/jacsau.4c00828 · Cited by 19
Motlová, L., Šnajdr, I., Kutil, Z., Andris, E., Ptacek, J., Novotná, A., Nováková, Z., Havlínová, B., Tueckmantel, W., Dráberová, H., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00212 · Cited by 14
Pandaram, A., Paul, J., Wankhar, W., Thakur, A., Verma, S., Vasudevan, K., Wankhar, D., Kammala, A. K., Sharma, P., Jaganathan, R., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12040855 · Cited by 19
“The binding site information was retrieved from literature evidence and the LPC CSU Server (https://oca.weizmann.ac.il/ oca-bin/lpccsu) accessed on 13 May 2023 [41].”
MethodXie, R., Tang, P., & Yuan, Q. (2017) · MedChemComm · doi:10.1039/c7md00476a · Cited by 20
Nencetti, S., Cuffaro, D., Nuti, E., Ciccone, L., Rossello, A., Fabbi, M., Ballante, F., Ortore, G., Carbotti, G., Campelli, F., et al. (2020) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2020.1835883 · Cited by 19
Kaur, M., Loveleen, & Kumar, R. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104396 · Cited by 18
Biaryl sulfonamides as cisoid azosteres for photopharmacology
Kobauri, P., Szymański, W., Cao, F., Thallmair, S., Marrink, . J., Witte, M. D., Dekker, F. J., & Feringa, B. L. (2021) · Chemical Communications · doi:10.1039/d1cc00950h · Cited by 19
Chi, Z., Lu, B., Liu, R., Chen, P., Meng, B., Xing, X., Yuan, H., Wu, X., Chen, Y., Ren, Y., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03400-y · Cited by 20
Anh, D. T., Pham‐The, H., Huy, L. D., Ngọc, H. B., Ngoc, T. T. M., Dung, D. T. M., Park, E. J., Song, I. K., Kang, J. S., Kwon, J., et al. (2021) · ACS Omega · doi:10.1021/acsomega.0c05870 · Cited by 18
Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment
Zhou, M., Zheng, H., Li, Y., Huang, H., Min, X., Dai, S., Zhou, W., Chen, Z., Xu, G., & Chen, Y. (2021) · Aging · doi:10.18632/aging.202554 · Cited by 20
“In the predicted HDAC6/Zeta55 structure, Zeta55 inserts into HDAC6 catalytic domain with its hydroxamate group, in a manner similar to HPOB binding in the HDAC6/HPOB crystal structure [16].”
Royce, S. G., Licciardi, P. V., Beh, R. C., Bourke, J. E., Donovan, C., Hung, A., Khurana, I., Liang, J. J., Maxwell, S., Mazarakis, N., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04609-3 · Cited by 19
“Docking was performed on the catalytic domain 2 of HDAC6 using PDB ID: 5EDU [57].”
MethodRužić, D., Petkovic, M., Djoković, N., Santibanez, J. F., Ellinger, B., Beljkaš, M., Gul, S., Djuric, A., Ganesan, A., Pavić, A., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122600 · Cited by 17
Palermo, A. F., Diennet, M., Ezzy, M. E., Williams, B. M., Cotnoir‐White, D., Mader, S., & Gleason, J. L. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.07.026 · Cited by 19
Raudszus, R., Nowotny, R., Gertzen, C. G. W., Schöler, A., Krizsan, A., Gockel, I., Kalwa, H., Gohlke, H., Thieme, R., & Hansen, F. K. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.07.055 · Cited by 17
“HDAC6 is the only isoform mainly located in the cytoplasm, is the only HDAC with two independent functional catalytic domains, and it is primarily acting via the deacetylation of non-histone substrates such as α-tubulin, cortactin or Hsp90.”
BackgroundGarcía, S., Mercado‐Sánchez, I., Córdova-Bahena, L., Alcaraz‐Contreras, Y., Garcia-Revilla, M. A., Robles, J., Santos-Martínez, N., Ordaz‐Rosado, D., Garcı́a-Becerra, R., & Vazquez, M. A. (2020) · Molecules · doi:10.3390/molecules25215134 · Cited by 21
Simoben, C. V., Ghazy, E., Zeyen, P., Darwish, S., Schmidt, M., Romier, C., Robaa, D., & Sippl, W. (2021) · Molecules · doi:10.3390/molecules26092584 · Cited by 17
“Nevertheless, some recently released crystal structures of HDAC6 isoform shows that some HDAC inhibitors coordinate the catalytic zinc ion in a mono-dentate fashion [47,48].”
BackgroundMarek, M., Ramos‐Morales, E., Picchi, G. F. A., Bayer, T., Norström, C., Herp, D., Sales-Junior, P. A., Guerra-Slompo, E. P., Hausmann, K., Chakrabarti, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110129 · Cited by 18
Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy
Li, X., Liu, X., Wang, S., Shi, X., Lü, M., Hao, X., Fu, Y., Zhang, Y., Jia, Q., & He, D. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.105874 · Cited by 20
Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents
El‐Awady, R., Saleh, E., Hamoudi, R., Ramadan, W. S. H., Mazitschek, R., Nael, M. A., Elokely, K. M., Abou-Gharbia, M. A., Childers, W. E., Srinivasulu, V., et al. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116251 · Cited by 17
Неганова, М. Е., Aleksandrova, Y. R., Суслов, Е. В., Mozhaitsev, E. S., Munkuev, A. A., Tsypyshev, D. O., Chicheva, M. M., Rogachev, A. D., Sukocheva, O. A., Volcho, K. P., et al. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13111893 · Cited by 17
Debnath, A., Mazumder, R., Mazumder, A., Singh, R. K., & Srivastava, S. (2023) · Letters in Drug Design & Discovery · doi:10.2174/1570180820666230125102954 · Cited by 16
Targeted Protein Degradation of Histone Deacetylases by Hydrophobically Tagged Inhibitors
Feller, F., & Hansen, F. K. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00468 · Cited by 18
Carullo, G., Orsini, N., Piano, I., Pozzetti, L., Papa, A., Fontana, A., Napoli, D., Corsi, F., Marco, B. D., Galante, A., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00477 · Cited by 18
Tavares, M. T., de Almeida, L. C., Kronenberger, T., Ferreira, G. M., de Divitiis, T. F., Toledo, M. F. Z. J., Hassimotto, N. M. A., Machado‐Neto, J. A., Costa-Lotufo, L. V., & Parise‐Filho, R. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116085 · Cited by 19
Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring
Moi, D., Citarella, A., Bonanni, D., et al. (2022) · RSC Advances · doi:10.1039/d2ra01753a · Cited by 16
Nguyen, H. P., Tran, Q. D., Nguyễn, C. Q., Hoa, T. P., Bình, T. D., Thao, H. N., Huê, B. T. B., Tuân, N. T., Đăng, Q. L., Nguyen, T. Q. C., et al. (2022) · RSC Advances · doi:10.1039/d2ra01969h · Cited by 15
Kraft, F. B., Enns, J., Honin, I., Engelhardt, J., Schöler, A., Smith, S. T., Meiler, J., Schäker‐Hübner, L., Weindl, G., & Hansen, F. K. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.107072 · Cited by 15
Liang, T., Liu, S., Dang, B., Luan, X., Guo, Y., Steimbach, R. R., Hu, J., Lu, L., Yue, P., Wang, R., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116624 · Cited by 15
Morgado, J., Diniz, L. P., Araújo, A. P. B., Antônio, L. M. D. S., Mota-Araujo, H. P., Pinheiro, P. D. S. M., Sagrillo, F. S., Vargas, G., Ferreira, S. T., Figueiredo, C. P., et al. (2024) · British Journal of Pharmacology · doi:10.1111/bph.16439 · Cited by 18
“The protein data bank high-resolution crystal structure 5EEN (1.86 Å) of HDAC6 catalytic domain 2 in complex with belinostat (Hai & Christianson, 2016) was selected for the docking studies.”
InfluentialStopper, D., Biermann, L., Watson, P. R., Li, J., König, B., Gaynes, M. N., de Carvalho, L. P., Klose, J., Hanl, M., Hamacher, A., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02373 · Cited by 20
Self-citationYue, K., Sun, S., Yin, Z., Liu, E., Jia, G., Jiang, Y., Duan, Y., Chen, Y., & Li, X. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02883 · Cited by 16
Structure–Activity Relationship of Propargylamine‐Based HDAC Inhibitors
Wünsch, M., Senger, J., Schultheisz, P., Schwarzbich, S., Schmidtkunz, K., Michalek, C., Klaß, M., Goskowitz, S., Borchert, P., Praetorius, L., et al. (2017) · ChemMedChem · doi:10.1002/cmdc.201700550 · Cited by 14
Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition
King, K., Hauser, A., Melesina, J., Sippl, W., & Jung, M. (2018) · Molecules · doi:10.3390/molecules23020321 · Cited by 15
“Crystal structures of human HDAC1 (PDB ID 5ICN) [17] and human HDAC6 catalytic domain 2 (PDB IDs 5EEN, 5EF8, 5GOI) [18,19] were used for the docking study and were downloaded from the Protein Data Bank (PDB) [25].”
MethodKashyap, K., & Kakkar, R. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1711191 · Cited by 16
Selg, C., Schöler, A., Schliehe‐Diecks, J., Hanl, M., Sinatra, L., Borkhardt, A., Sárosi, M. B., Bhatia, S., Hey‐Hawkins, E., & Hansen, F. K. (2021) · Chemical Science · doi:10.1039/d1sc02268g · Cited by 15
Varga, J. K., Diffley, K., Leng, K. W., Fierke, C. A., & Schueler‐Furman, O. (2022) · Scientific Reports · doi:10.1038/s41598-022-05681-2 · Cited by 17
“Comparison of the KDAC6 (PDB ID: 5EFN [5]) and KDAC8 (PDB ID: 2V5W [68] structures (Figure 2) highlight two main differences in loops involved in forming the binding pocket that could lead to differences in binding selectivity.”
BackgroundMethodInfluentialAvrahami, E. M., Levi, S., Zajfman, E., Regev, C., Ben‐David, O., & Arbely, E. (2018) · ACS Synthetic Biology · doi:10.1021/acssynbio.8b00314 · Cited by 15
Sharma, M., Jha, P. K., Verma, P., & Chopra, M. (2019) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13488 · Cited by 15
“Based on the earlier studies (Bertrand, 2010) and the cocrystallized ligand TSA with the HDAC6 receptor (Hai & Christianson, 2016), the active site was found to be usually located in a hydrophobic cleft of amino acids: Phe620, Phe680, Leu749, Pro501 and His500.”
BackgroundMethodInfluentialAbdulwahab, H. G., Mansour, R. E., Farghaly, T. A., & El-Sehrawi, H. M. A. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107284 · Cited by 14
Geurs, S., Clarisse, D., Baele, F., Franceus, J., Desmet, T., Bosscher, K. D., & D’hooghe, M. (2022) · Chemical Communications · doi:10.1039/d2cc01550a · Cited by 20
The epigenetic landscape of rheumatoid arthritis: Pathogenesis and drug therapeutic potentials
Huang, C., Liang, Y., Li, Y., Quan, W., Ouyang, L., & Zhang, J. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.08.022 · Cited by 20
“To enhance the selectivity of HDAC6 inhibition, a design incorporating a large and rigid cap group is essential to adequately occupy the rim region of HDAC6, along with a short and wide linker that fits snugly within the catalytic channel 229,230 .”
Pioneering first‐in‐class FAAH‐HDAC inhibitors as potential multitarget neuroprotective agents
Papa, A., Cursaro, I., Pozzetti, L., Contri, C., Cappello, M., Pasquini, S., Carullo, G., Ramunno, A., Gemma, S., Varani, K., et al. (2023) · Archiv der Pharmazie · doi:10.1002/ardp.202300410 · Cited by 17
Antibody drug conjugates beyond cytotoxic payloads
Hobson, A. D. (2023) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2023.10.001 · Cited by 15
Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs
Stopper, D., Honin, I., Feller, F., & Hansen, F. K. (2025) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5c00033 · Cited by 14
Hu, Z., Li, S., He, H., Pan, W., Liu, T., Liang, H., Xu, C., Lu, B., Tao, C., Qi, Z., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02510 · Cited by 13
Wurnig, S. L., Hanl, M., Geiger, T. M., Zhai, S., Dressel, I., Pieńkowska, D. E., Nowak, R. P., & Hansen, F. K. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00972j · Cited by 14
Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa
Krämer, A., Wagner, T., Yıldız, Ö., & Meyer‐Almes, F. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00613 · Cited by 14
Zhao, L., Fu, L., Li, G., Yu, Y., Wang, J., Liang, H., Shu, M., Lin, Z., & Wang, Y. (2022) · Molecular Diversity · doi:10.1007/s11030-022-10474-w · Cited by 14
“2), which has higher crystal quality [35].”
BackgroundOsko, J. D., Roose, B. W., Shinsky, S. A., & Christianson, D. W. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00582 · Cited by 13
Self-citationDawood, M., Hegazy, M. F., Elbadawi, M., Fleischer, E., Klinger, A., Bringmann, G., Kuntner, C., Shan, L., & Efferth, T. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114176 · Cited by 13
Prejanò, M., Vidossich, P., Russo, N., Vivo, M. D., & Marino, T. (2021) · ACS Catalysis · doi:10.1021/acscatal.0c04729 · Cited by 15
Kumar, M., Joshi, G., Chatterjee, J., & Kumar, R. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200207100227 · Cited by 15
Harding, R., Franzoni, I., Mann, M. K., Szewczyk, M. M., Mirabi, B., de Freitas, R. F., Owens, D. D. G., Ackloo, S. Z., Scheremetjew, A., Juárez‐Ornelas, K. A., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00314 · Cited by 15
Gupta, S., Ali, K. H., Lee, S., & Seo, Y. H. (2023) · Archives of Pharmacal Research · doi:10.1007/s12272-023-01467-w · Cited by 12
“We conducted a molecular docking study of compounds 3a and 3b at the active site of HDAC6 to investigate their precise binding positions on HDAC6 (PDB code: 5EF7) (Hai and Christianson 2016).”
BackgroundMethodInfluentialTretbar, M., Schliehe‐Diecks, J., von Bredow, L., Tan, K., Roatsch, M., Tu, J., Kemkes, M., Sönnichsen, M., Schöler, A., Borkhardt, A., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116447 · Cited by 11
Mechanistic and Structural Insights on Difluoromethyl-1,3,4-oxadiazole Inhibitors of HDAC6
Cellupica, E., Gaiassi, A., Rocchio, I., Rovelli, G., Pomarico, R., Sandrone, G., Caprini, G., Cordella, P., Cukier, C. D., Fossati, G., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115885 · Cited by 14
“…the anionic form of the hydroxamic OH group, whereas bidenticity is typically observed in complexes where the inhibitor exhibits an aliphatic chain [10,17,19] bound to the hydroxamate group and involves both oxygen atoms of the warhead, thus displacing the catalytic water from the Zn ion…”
BackgroundFischer, F., Schliehe‐Diecks, J., Tu, J., Gangnus, T., Ho, Y. L., Hebeis, M., Avelar, L. A. A., Scharov, K., Watrin, T., Kemkes, M., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02024 · Cited by 14
Selective Inhibitors of Histone Deacetylase 10 (HDAC-10)
Pojani, E., & Barlocco, D. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210901144658 · Cited by 12
Aleksandrova, Y. R., Munkuev, A. A., Mozhaitsev, E. S., Суслов, Е. В., Tsypyshev, D. O., Chaprov, K., Бегунов, Р. С., Volcho, K. P., Salakhutdinov, N. F., & Неганова, М. Е. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119743 · Cited by 14
“Taking into account the spectrum of action of the catalytic domain 2 [45] and the literature data on in silico procedures [46], the structure of the HDAC6 complex and trichostatin A bound to a protein in the second catalytic domain [47] was used for docking procedures.”
MethodAnticancer Ruthenium Complexes with HDAC Isoform Selectivity
Cross, J. M., Blower, T. R., Kingdon, A. D. H., Pál, R., Picton, D. M., & Walton, J. W. (2020) · Molecules · doi:10.3390/molecules25102383 · Cited by 12
“The m re bulky and more hydrophobic tolyl group likely provides more favourable interacti n with the catalytic channel rim of HDAC6, which is known to be wider and shallower than other HDAC isoforms [33].”
BackgroundInfluentialKhamis, M. Y., Wu, H.-P., Ma, Q., Li, Y., Ma, L., Zhang, X., & Liu, H. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.104754 · Cited by 12
Rational Design and Development of HDAC Inhibitors for Breast Cancer Treatment
Mody, D., Bouckaert, J. M. J., Savvides, S. N., & Gupta, V. (2021) · Current Pharmaceutical Design · doi:10.2174/1381612827666210917143953 · Cited by 13
“This imparts spatial restriction to allow selective entry of acetyllysine peptide substrates in CD1, rationalizing its narrowed specificity.”
BackgroundInfluentialKhoury, L. E., Naseem‐Khan, S., Kwapień, K., Hobaika, Z., Maroun, R. G., Piquemal, J., & Gresh, N. (2017) · Journal of Computational Chemistry · doi:10.1002/jcc.24830 · Cited by 12
Structure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer
Citarella, A., Belluti, S., Bonanni, D., Moi, D., Piccinini, I., Rinaldi, A., Papulino, C., Benedetti, R., Cuoghi, L., Ciolo, S. D., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00717 · Cited by 11
“41 Conversely, five-membered heterocyclic compounds are predicted to preferentially coordinate the Zn 2+ ion in a bidentate fashion (Figure 6, panel B), comparable to various crystallographic structures of ligand complexes with similar linkers.”
Novel histone deacetylase 6 inhibitors using benzimidazole as caps for cancer treatment
Nguyen, P. H., Huê, B. T. B., Quân, P. M., Hoa, T. P., Tran, Q. D., Jung, H., Hieu, L. T., Nguyễn, C. Q., Hong, V. Q., Quy, N. P., et al. (2023) · New Journal of Chemistry · doi:10.1039/d2nj05731j · Cited by 11
Mansour, R. E., Abdulwahab, H. G., & El-Sehrawi, H. M. A. (2023) · Archiv der Pharmazie · doi:10.1002/ardp.202200433 · Cited by 11
Histone deacetylase 10: A polyamine deacetylase from the crystal structure to the first inhibitors
Lambona, C., Zwergel, C., Fioravanti, R., Valente, S., & Mai, A. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102668 · Cited by 11
Jin, X. Y., Wang, Y., Chen, J., Niu, M., Yang, Y., Zhang, Q., & Bao, G. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2023.2289355 · Cited by 11
A quantitative model for virus uncoating predicts influenza A infectivity
Artcibasova, A. V., Wang, L., Anchisi, S., Yamauchi, Y., Schmolke, M., Matthias, P., & Stelling, J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113558 · Cited by 11
Epigenetic-based differentiation therapy for Acute Myeloid Leukemia
José‐Eneriz, E. S., Gimenez-Camino, N., Rabal, O., Gárate, L., Miranda, E., Gómez-Echarte, N., Garcı́a, F., Charalampopoulou, S., Sáez, E., Vilas‐Zornoza, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49784-y · Cited by 11
Identification of novel cyclin-dependent kinase 4/6 inhibitors from marine natural products
Debnath, A., Mazumder, R., Singh, A. K., & Singh, R. K. (2025) · PLoS ONE · doi:10.1371/journal.pone.0313830 · Cited by 12
“The catalytic domain and binding site residues (ILE19, TYR24, ALA41, GLU99, GLN103, ASP104, and ALA162) of the CDK4/6 complex were elucidated through a comprehensive analysis of previously published literature [31–33], (PDB identifier: 5L2S).”
Asaad, L., Pepperrell, B., McErlean, E. M., & Furlong, F. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031274 · Cited by 11
“However, the CD2 domain of HDAC6 is considered to be the main catalytic site and bears a wider substrate specificity compared to the CD1 site [4].”
Zhang, Y., Fu, T., Ren, Y., Li, F., Zheng, G., Hong, J., Yao, X., Xue, W., & Zhu, F. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00041 · Cited by 12
“HDAC1and6 Structures On the basis of the resolved protein crystals of HDAC1&6 available in Protein Data Bank (PDB) (Hai and Christianson, 2016; Watson et al., 2016), there were 75 and 68 binding poses of FK228 in HDAC1 and HDAC6 generated by molecular docking, respectively.”
BackgroundMethodInfluentialImmobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors
Roth, L., Gotsbacher, M. P., & Codd, R. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01541 · Cited by 10
Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations
Mishra, A., & Singh, A. (2022) · ACS Omega · doi:10.1021/acsomega.2c01572 · Cited by 12
Poonia, P., Sharma, M., Jha, P. K., & Chopra, M. (2022) · Molecular Diversity · doi:10.1007/s11030-022-10540-3 · Cited by 11
“Another PDB ID 5EF7 was also downloaded (Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with HPOB) [74].”
BackgroundMethodInfluentialChemically Diverse S. mansoni HDAC8 Inhibitors Reduce Viability in Worm Larval and Adult Stages
Noce, B., Bello, E. D., Zwergel, C., Fioravanti, R., Valente, S., Rotili, D., Masotti, A., Ansari, M. S. Z., Trisciuoglio, D., Chakrabarti, A., et al. (2022) · ChemMedChem · doi:10.1002/cmdc.202200510 · Cited by 11
Toro, T. B., Bryant, J. R., & Watt, T. J. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00270 · Cited by 11
“We are unaware of any direct comparison of peptides with and without the AMC fluorophore for KDAC6, but prior data characterizing steady-state kinetics of KDAC6 resulted in KM values similar to those we observed, with AMC-containing peptides consistently much lower than unlabeled peptides and with relatively little va…”
Novel α,β-unsaturated hydroxamic acid derivatives overcome cisplatin resistance
Pflieger, M., Hamacher, A., Öz, T., et al. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.07.052 · Cited by 11
Caballero-Camino, F. J., Rivilla, I., Herráez, E., Briz, Ó., Santos‐Laso, Á., Izquierdo‐Sánchez, L., Lee, P. Y., Rodrigues, P. M., Muñoz-Garrido, P., Jin, S., et al. (2020) · Hepatology · doi:10.1002/hep.31216 · Cited by 13
“We applied our previously described HDAC inhibition model(21) to the X-ray structure of the catalytic domain 2 of human HDAC6 (PDB code: 5EDU)(22) (Fig.”
MethodYan, G., Li, D., Zhong, X.-X., Liu, G., Wang, X., Lu, Y., Qin, F., Guo, Y., Duan, S., & Li, D. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1743760 · Cited by 11
“The crystal structure of HDAC6 combined with Trichostatin A (pdb:5EDU) (Hai & Christianson, 2016) was downloaded from RCSB (www.rcsb.org).”
MethodWatson, P. R., Bai, P., Wang, C., Cragin, A. D., Hooker, J. M., & Christianson, D. W. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00332 · Cited by 15
Self-citationPichlak, M., Sobierajski, T., Błażewska, K. M., & Gendaszewska‐Darmach, E. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2023.2254012 · Cited by 10
HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents
Waitman, K. B., de Almeida, L. C., Primi, M. C., Carlos, J. A. E. G., Ruiz, C. H., Kronenberger, T., Laufer, S., Goettert, M. I., Poso, A., Vassiliades, S. V., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115935 · Cited by 10
Uba, A. İ., Hryb, M., Singh, M., Bui-Linh, C., Tran, A., Atienza, J., Misbah, S., Mou, X., & Wu, C. F. (2024) · Life Sciences · doi:10.1016/j.lfs.2023.122395 · Cited by 11
Santini, A., Tassinari, E., Poeta, E., Loi, M., Ciani, E., Trazzi, S., Piccarducci, R., Daniele, S., Martini, C., Pagliarani, B., et al. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00061 · Cited by 9
Yang, F., Liu, J., Xu, X.-L., Hu, T., Liu, J., He, Z., Zhao, G., Wei, B., & Ma, L. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01168 · Cited by 11
Pang, N., Sun, J., Che, S., & Yang, N. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102068 · Cited by 11
“The initial structure of the two systems was derived from the crystal structure of ScHos3 determined in this work and the CD2 domain of the crystal structure of hHDAC6 (deduced from PDB ID: 5EDU by the removal of the MBP tag and TSA) (43), respectively.”
MethodWatson, P. R., Stollmaier, J. G., & Christianson, D. W. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105228 · Cited by 11
“The initial electron density map was phased by molecular replacement using Phaser (53) with the atomic coordinates of unliganded HDAC6 (PDB 5EEM) (21) as a search probe for rotation and translation function calculations (PDB 5EEM).”
BackgroundMethodSelf-citationNi, D., Wang, Q., Li, Y., Cui, Y.-M., Shen, T., Li, X., Sun, H., Zhang, X., Zhang, R., & Xiao, W. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.104728 · Cited by 10
Hernández, F., Mercado‐Sánchez, I., Alcaraz‐Contreras, Y., Garcia-Revilla, M. A., Gómez, C. V., Ordaz‐Rosado, D., Santos-Martínez, N., Garcı́a-Becerra, R., & Vazquez, M. A. (2021) · DARU Journal of Pharmaceutical Sciences · doi:10.1007/s40199-021-00406-8 · Cited by 10
Watson, P. R., & Christianson, D. W. (2023) · Biochemistry · doi:10.1021/acs.biochem.3c00288 · Cited by 9
Self-citationChoudhary, G. P., Prajapat, M., Kaur, G., Singh, H., Mahendiratta, S., Prakash, A., & Medhi, B. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2274518 · Cited by 10
“The CD2 pocket is of clinical interest due to its relevance to the investigation (Hai & Christianson, 2016).”
Influentialvon Bredow, L., Schäfer, T. M., Hogenkamp, J., Tretbar, M., Stopper, D., Kraft, F. B., Schliehe‐Diecks, J., Schöler, A., Borkhardt, A., Bhatia, S., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15030333 · Cited by 10
“To shed light into this phenomenon, we docked (α)-7c and (β)-7c into the second catalytic domain of HDAC6 (PDB: 5EDU [29]).”
BackgroundInfluentialDiscovery of selective HDAC6 inhibitors based on a multi-layer virtual screening strategy
Liu, X., Yan, W., Wang, S., Lu, M., Yang, H., Chai, X., Shi, H., Zhang, Y., & Jia, Q. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107036 · Cited by 9
Class I histone deacetylase complex: Structure and functional correlates
Wang, X. D., Wang, Y., Liu, S., Zhang, Y., Xu, K., Ji, L., Kornberg, R. D., & Zhang, H. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307598120 · Cited by 9
“The map contained density for a metal ion, presumably a zinc ion, and a water molecule, anticipated from previous studies (26, 27) (Fig.”
Metadata
- Authors
- Hai, Y., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Harvard University (US)
- Corresponding author
- Christianson, David W
- Venue
- Nature Chemical Biology
- Published
- 2016-07-25
- Volume
- 12
- Issue
- 9
- Pages
- 741-747
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4990478
- OpenAlex
- W2499955277
- Cited by
- 521
- References
- 61
- Citations by year
- 2026: 56 · 2025: 76 · 2024: 50 · 2023: 55 · 2022: 47 · 2021: 57 · 2020: 54 · 2019: 46 · 2018: 42 · 2017: 29 · 2016: 9
- FWCI
- 23.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM049758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- HDAC6, crystal structure, substrate specificity, catalytic mechanism, belinostat, panobinostat, HC-toxin, zinc coordination, small molecule inhibitors, cancer drug targets
- MeSH terms
- Animals, Histone Deacetylases, Humans, Models, Molecular, Structure-Activity Relationship, Substrate Specificity, Zebrafish, Molecular Structure, Biocatalysis, Histone Deacetylase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
