CoChat
Sign Up
Cited by 713Histone Deacetylase Inhibitors ResearchEnzyme Structure and FunctionEnzyme function and inhibition

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor

Open access
Vannini, Alessandro, Volpari, Cinzia, Filocamo, Gessica, Casavola, Elena Caroli, Brunetti, Mirko, Renzoni, Debora, Chakravarty, Prasun, Paolini, Chantal +4 more·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0404603101PMC PMC524051
Open this paper in CoChat — free account

Abstract

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single α/β domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper reports the crystal structure of human HDAC8, a eukaryotic zinc-dependent histone deacetylase, in complex with a hydroxamic acid inhibitor, revealing a single α/β domain, a pentacoordinated active-site Zn²⁺, and two bound K⁺ ions. It also shows that HDAC8 has a distinct inhibitor profile and that siRNA knockdown of HDAC8 inhibits proliferation of A549, HeLa, and HCT116 tumor cell lines.

Key findings

  • The HDAC8 monomer folds as a single compact α/β domain with a central eight-stranded parallel β-sheet and 11 α-helices; the crystal contains a head-to-head dimer burying ≈1,300 Ų, but size-exclusion chromatography and light scattering are compatible with a monomer in solution. The active-site Zn²⁺ is pentacoordinated by Asp-178, His-180, Asp-267, and the hydroxamate inhibitor.
  • Two K⁺ sites were identified: site 1 is 7.0 Å from the zinc site and site 2 is 15 Å from site 1, with peaks of 19σ and 13σ, respectively. K⁺ site 1 contacts backbone carbonyls of Asp-178 and His-180, whose side chains coordinate zinc. CD spectroscopy showed a melting midpoint of ≈35.5°C in NaCl versus ≈41°C in KCl.
  • HDAC8 inhibition differed from HDAC1 and HDAC3: IC₅₀ values for HDAC8/HDAC1/HDAC3 were TSA 490/1.5/0.6 nM, SAHA 4,000/119/106 nM, Compound 1 175.5/86.0/44 nM, MS27-275 >10,000/185/201 nM, and apicidin >1,000/2/0.7 nM. Compound 1 showed relatively similar potency across all three enzymes (<4-fold differences).
  • Two HDAC8 siRNAs inhibited proliferation in A549, HeLa, and HCT116 cells; an Eg5 siRNA gave comparable growth inhibition, whereas an unrelated Luc siRNA had no effect.

Methods

  • Human HDAC8 was expressed and purified, then crystallized after incubation of 130 μM HDAC8 with a 6.7 molar excess of inhibitor for 1 h at room temperature. Crystals were grown by sitting-drop vapor diffusion; data were collected at 100 K using synchrotron radiation.
  • The structure was solved by molecular replacement using a truncated homology model of HDAC8 residues 63–320 based on the HDLP–TSA structure (PDB 1C3R), and refined to 2.5 Å with final R and R_free of 0.21 and 0.25.
  • CD spectroscopy measured thermal unfolding in KCl- or NaCl-containing buffers. siRNA transfection and cell-growth assays were performed in A549, HeLa, and HCT116 cells; HDAC inhibition assays tested HDAC1, HDAC3, and HDAC8 against a panel of inhibitors.

Limitations

  • The paper states no formal limitations section. It notes that the crystal dimer is mediated by the inhibitor and is unlikely to occur in solution, and that the relevance of potassium-binding site 2 for catalytic activity is not obvious from the structure.
  • Evident from the text: the structural conclusions come from one 2.5-Å crystal form; potassium-binding site 1 was identified at 75 mM K⁺ in the crystallization drop, lower than the intracellular physiological value of ≈150 mM; and the RNAi proliferation data are limited to three human tumor cell lines with no in vivo results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1073/pnas.0404603101

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 5 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Potassium-binding site 2 is formed by the main-chain carbonyl oxygen of residues Phe-189, Thr-192, Val-195, and Tyr-225 and two water molecules.

    “Potassium-binding site 2 ([Fig. 6*B*](#fig6)) is formed by the main-chain carbonyl oxygen of residues Phe-189, Thr-192, Val-195, and Tyr-225 and two water molecules.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Compound 1 showed relatively similar potencies (<4-fold differences) on HDAC8, HDAC1, and HDAC3.

    “Compound 1, an aryl hydroxamic acid identified by screening a collection of small molecules, instead showed relatively similar potencies (<4-fold differences) on all tested proteins.”
    Quote in the paperSubstantial claim
  • Findingown data

    The active site of HDAC8 reveals an ≈12-Å-deep, narrow pocket likely to accommodate the acetylated lysine during the catalytic reaction.

    “In the active site, the van der Waals surface of the enzyme reveals an ≈12-Å-deep, narrow pocket likely to accommodate the acetylated lysine during the catalytic reaction.”
    Quote in the paperSubstantial claim
  • Findingown data

    Potassium-binding site 1 is directly connected with the zinc-binding site, because the K+ ion is coordinated by the main-chain carbonyl oxygens of Asp-178 and His-180, whose side chains are involved in zinc chelation.

    “Potassium-binding site 1 is directly connected with the zinc-binding site, because the K+ ion is coordinated by the main-chain carbonyl oxygens of Asp-178 and His-180, whose side chains are involved in zinc chelation ([Fig. 4*A*](#fig4)).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The capping groups interact with protein residues Pro-273 and Tyr-306 of the opposite molecule, forming an extensive hydrophobic sandwich.

    “each capping group interacts with protein residues Pro-273 and Tyr-306 of the opposite molecule, forming an extensive hydrophobic sandwich”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 6
  • May combine two claims. 22
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Residues at potassium-binding site 1 are conserved in all zinc-dependent HDACs, with the exception of Leu-200, which can be substituted with Phe (HDAC1, -2, and -3) or Trp (HDAC10).

    “Residues at potassium-binding site 1 are conserved in all zinc-dependent HDACs, with the exception of Leu-200, which can be substituted with Phe (HDAC1, -2, and -3) or Trp (HDAC10).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Each HDAC8 molecule binds one Zn2+ ion and two K+ ions.

    “Each molecule binds one Zn2+ ion and two K+ ions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In HDAC8, the loop region equivalent to Pro-22 from HDLP is shorter, so the interaction with the capping group of TSA inhibitor is not possible.

    “the loop region featuring the equivalent of Pro-22 from HDLP (Ala-32 in HDAC8), a residue that interacts with the capping group of TSA inhibitor ([11](#ref11)), is shorter in HDAC8, and therefore this interaction is not possible ([Fig. 2*C*](#fig2))”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Finnin, M. S., Donigian, J. R., Cohen, A., Richon, V. M., Rifkind, R. A., Marks, P. A., Breslow, R. & Pavletich, N. P. (1999) Nature 401**,** 188–193. [[DOI](https://doi.org/10.1038/43710)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/10490031/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nature&volume=401&publication_year=1999&pages=188&pmid=10490031&doi=10.1038/43710&)] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    HDAC8 folds in a single α/β domain, similar to bacterial HDAC-like protein.

    “Similar to bacterial HDAC-like protein, HDAC8 folds in a single α/β domain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    All residues contacting the linker are conserved except for Met-274, which is a Leu in all other class I and II HDACs with the exception of HDAC10, which has a Glu in this position.

    “All residues contacting the linker are conserved except for Met-274, which is a Leu in all other class I and II HDACs with the exception of HDAC10, which has a Glu in this position.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The HDAC8 structure contains two potassium ions, one of which interacts with key catalytic residues.

    “including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The loop 332-345 is 10 residues shorter than that observed in HDLP, leaving the active site less shielded from one side.

    “Most strikingly, the loop 332–345, part of the long extended linker between α10 and -11, is 10 residues shorter than that observed in HDLP, leaving the active site less shielded from one side”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The two potassium-binding sites are placed on the same face of the β-sheet and contribute equally to anchoring helix α7 and its loops to the central β-sheet.

    “The two potassium-binding sites are placed on the same face of the β-sheet and contribute equally to anchoring helix α7 and its loops to the central β-sheet ([Fig. 6*B*](#fig6)).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The cyclic linker region of the inhibitor fits in the hydrophobic channel, with its aromatic aryl moiety stacked between side chains of Phe-152 and -208.

    “The cyclic linker region of the inhibitor fits in the hydrophobic channel, with its aromatic aryl moiety stacked between side chains of Phe-152 and -208.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    TSA and SAHA are poor HDAC8 inhibitors.

    “TSA and SAHA, both poor HDAC8 inhibitors ([Table 1](#tbl1))”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The structure of HDAC8 reveals K+ ions bound at two sites: site 1 is 7.0 Å from the zinc-binding site, and site 2 is 15 Å away from site 1.

    “Unexpectedly, the structure of HDAC8 reveals K+ ions bound at two sites: Site 1 is in close proximity (7.0 Å) to the zinc-binding site, whereas site 2 is located more toward the periphery of the molecule, 15 Å away from site 1 ([Fig. 6*B*](#fig6)).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Residues forming the two potassium-binding sites come from loops contiguous to helix α7 (Asp-178 and His-180 at site 1; Phe-189 and Thr-192 at site 2) and from strands β4, -5, and -6 (Asp-176, Ser-199, and Leu-200 at site 1; Val-195 and Tyr-225 at site 2).

    “Residues forming the two potassium-binding sites come from loops contiguous to helix α7 (Asp-178 and His-180 at site 1; Phe-189 and Thr-192 at site 2) and from strands β4, -5, and -6 (Asp-176, Ser-199, and Leu-200 at site 1; Val-195 and Tyr-225 at site 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The structures of human HDAC8 with four inhibitors described by Somoza et al. are comparable to ours.

    “The authors describe the structure of human HDAC8 with four inhibitors. Their structures are comparable to ours.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Somoza, J. R., Skene, R. J., Katz, B. A., Mol, C., Ho, J. D., Jennings, A. J., Luong, C., Arvai, A., Buggy, J. J., Chi, E., *et al.* (2004) Structure 7**,** 1325–1334. [[DOI](https://doi.org/10.1016/j.str.2004.04.012)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15242608/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Structure&volume=7&publication_year=2004&pages=1325&pmid=15242608&doi=10.1016/j.str.2004.04.012&)]

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Size-exclusion chromatography and light-scattering experiments are compatible with a monomeric state for both the apoprotein and the protein-inhibitor complex.

    “the results of size-exclusion chromatography and light-scattering experiments are compatible with a monomeric state for both the apoprotein and the protein–inhibitor complex (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The capping group of the inhibitor is oriented toward pocket d and points toward the solvent, not interacting with the protein.

    “The capping group of the inhibitor is oriented in the direction of pocket d, even if this moiety does not interact with the protein but points toward the solvent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    The sequence conservation at site 2 is somewhat lower than at site 1: Thr-192 is Asp in class II HDACs; Val-195 is different only in HDAC9 (Ile); and Tyr-225 is different only in HDAC10 (Phe).

    “The sequence conservation at this site is somewhat lower than at site 1: Thr-192 is Asp in class II HDACs; Val-195 is different only in HDAC9 (Ile); and Tyr-225 is different only in HDAC10 (Phe).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The presence of K+ in the active site can be expected to influence the catalytic mechanism of the deacetylation reaction in several aspects.

    “The presence of K+ in the active site can be expected to influence the catalytic mechanism of the deacetylation reaction in several aspects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The exchange with Na+ ions could alter the overall folding of the enzyme, in agreement with the decreased protein stability observed when the protein was purified in the presence of NaCl.

    “The exchange with Na+ ions, which share with K+ the same external electronic configuration but a remarkably smaller ionic radius, could alter the overall folding of the enzyme, in agreement with the decreased protein stability observed when the protein was purified in the presence of NaCl (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Trp-141 is replaced by Leu in HDAC1 and -3, which should leave more space to accommodate MS27-275 and is in line with the increased potency toward HDAC1 and -3.

    “Trp-141 is replaced by Leu in HDAC1 and -3, which should leave more space to accommodate this inhibitor and is in line with the increased potency toward HDAC1 and -3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    By analogy to Ca2+-binding proteins, upon chelation with the cation, the two CO bonds of the Asp-176 side chain no longer should be equivalent, with the bond of the chelating oxygen having more single-bond character and that of the nonchelating oxygen, hydrogen-bonded to His-142, more double-bond character.

    “By analogy to Ca2+-binding proteins ([20](#ref20)), upon chelation with the cation, the two CO bonds of the Asp-176 side chain no longer should be equivalent, with the bond of the chelating oxygen having more single-bond character and that of the nonchelating oxygen, hydrogen-bonded to His-142, more double-bond character.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Mizuguchi, M., Nara, M., Kawano, K. & Nitta, K. (1997) FEBS Lett. 417**,** 153–156. [[DOI](https://doi.org/10.1016/s0014-5793(97)01274-x)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9395095/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=FEBS%20Lett.&volume=417&publication_year=1997&pages=153&pmid=9395095&doi=10.1016/s0014-5793(97)01274-x&)]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The two potassium sites were identified by strong positive peaks (19 and 13 σ) in the Fo - Fc maps and had typical distances and hexacoordination geometry for potassium binding.

    “The two sites were identified by strong positive peaks (19 and 13 σ, respectively) in the *F*o – *F*c maps and had typical distances and hexacoordination geometry for potassium binding ([19](#ref19)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Harding, M. M. (2002) Acta Crystallogr. D 58**,** 872–874. [[DOI](https://doi.org/10.1107/s0907444902003712)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/11976508/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Acta%20Crystallogr.%20D&volume=58&publication_year=2002&pages=872&pmid=11976508&doi=10.1107/s0907444902003712&)] source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    The increased potency of TSA and SAHA on HDAC1 and -3 with respect to HDAC8 is in line with the finding that most HDACs have a Pro at this position.

    “This finding is in line with the increased potency of TSA and SAHA observed on HDAC1 and -3 with respect to HDAC8.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The coordinates and structure factors have been deposited in the Protein Data Bank (PDB ID code 1W22).

    “Data deposition: The coordinates and structure factors have been deposited in the Protein Data Bank, [www.pdb.org](http://www.pdb.org) (PDB ID code 1W22).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The presence of K+ increases the positive electrostatic potential in the active site and therefore could contribute to stabilize the oxyanion formed in the transition state of the deacetylation reaction and/or to stabilize the negatively charged acetate product.

    “First, its presence increases the positive electrostatic potential in the active site and therefore could contribute to stabilize the oxyanion formed in the transition state of the deacetylation reaction and/or to stabilize the negatively charged acetate product.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The final concentration of K+ ions in the crystallization drop is 75 mM, lower than the intracellular physiological value of ≈150 mM, suggesting that the potassium-binding sites could be biologically relevant.

    “The final concentration of K+ ions in the crystallization drop is 75 mM, a value lower than its intracellular physiological value of ≈150 mM, suggesting that the potassium-binding sites could be biologically relevant.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The intracellular physiological K+ concentration is approximately 150 mM.

  • May combine two claims.

    Interpretationcitation

    These chains act as optimal linkers for the hydroxamic acid and the capping group, allowing contacts both at the bottom and the entrance of the pocket.

    “These chains act as optimal linkers for the hydroxamic acid and the capping group, allowing contacts both at the bottom and the entrance of the pocket.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Structural variability in the loop regions emerging from the conserved core will be found across the entire family of HDACs.

    “It is conceivable that structural variability in the loop regions emerging from the conserved core will be found across the entire family of HDACs”
    Quote in the paperNot a substantial claim
27 of 27

  • The paper relies on this without support.

    No structure of a eukaryotic zinc-dependent HDAC had been described before this study.

    “Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously.”

  • The paper relies on this without support.

    The dimeric arrangement seen in the crystal has not been found in solution.

    “given that the dimeric arrangement seen in the crystal has not been found in solution”

  • The paper relies on this without support.

    The intracellular physiological K+ concentration is approximately 150 mM.

    “a value lower than its intracellular physiological value of ≈150 mM”
3 of 3

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?

  • Crystal structures of human HDAC8 in complex with different inhibitors revealed a single α/β-domain with a core eight-stranded parallel β-sheet and 11 α-helices.

    “Crystal structures of human HDAC8, in complex with different inhibitors, have been reported; they revealed a single α/β-domain with a core eight-stranded parallel β-sheet and 11 α-helices.7, 31, 32”

    From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [7]

  • HDAC8 affects cell proliferation in different tumor types.

    “More generally, HDAC8 affects cell proliferation in different tumor types (Vannini et al., 2004).”

    From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Vannini et al., 2004

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.

  • HDAC8 is both described as having Ala and included among enzymes with Pro at the same position

    Minor

    The paper identifies Ala-32 in HDAC8 as equivalent to Pro-22 in HDLP, then says that all class I and II HDACs except HDAC10 have Pro at that position. HDAC8 is identified elsewhere in the paper as a class I HDAC.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Somoza, J. R., Skene, R. J., Katz, B. A., Mol, C., Ho, J. D., Jennings, A. J., Luong, C., Arvai, A., Buggy, J. J., Chi, E., et al. (2004) Structure 7, 1325–1334.

Cited by

Sorted by citations

Related

Authors
Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., Steinkühler, C., & Di Marco, S.
Affiliations
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-10-11
Volume
101
Issue
42
Pages
15064-15069
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0404603101
PMC
PMC524051
OpenAlex
W2078454854
Semantic Scholar
03c10a313fe9a3fe15c2052dfba5f2319155ebba
Cited by
638
References
23
Citations by year
2026: 19 · 2025: 13 · 2024: 25 · 2023: 17 · 2022: 18 · 2021: 19 · 2020: 23 · 2019: 27 · 2018: 20 · 2017: 27 · 2016: 34 · 2015: 37 · 2014: 30 · 2013: 34 · 2012: 40
FWCI
9.87
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords
HDAC8, histone deacetylase, hydroxamate inhibitors, zinc metalloenzyme, crystal structure, potassium ions, active site, anticancer agents, histone deacetylase inhibitors, tumor cell proliferation, RNAi knockdown
MeSH terms
Amino Acid Sequence, Antineoplastic Agents, Circular Dichroism, Enzyme Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Models, Molecular, Molecular Sequence Data, Potassium, Protein Conformation, Recombinant Proteins, Repressor Proteins, Zinc, Drug Design, Sequence Homology, Amino Acid, Crystallography, X-Ray, Catalytic Domain, RNA Interference, Cell Line, Tumor, Histone Deacetylase Inhibitors, In Vitro Techniques

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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