The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index; none of the 25 sources its claims cite is checked for support yet.
Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125
Open accessAbstract
The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism. The van der Waals contacts by the three residues (Pro157, Leu160, and Leu162) of pepJIP1 and the hydrogen bonding between Glu329 of JNK1 and Arg156 of pepJIP1 are critical for the selective binding. Binding of the peptide also induces a hinge motion between the N- and C-terminal domains of JNK1 and distorts the ATP-binding cleft, reducing the affinity of the kinase for ATP. In addition, we also determined the ternary complex structure of pepJIP1-bound JNK1 complexed with SP600125, an ATP-competitive inhibitor of JNK, providing the basis for the JNK specificity of the compound.
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30 Own result · 26 Own interpretation · 20 Not checked yet · 3 No basis given · 1 Own method
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“Binding of the peptide also induces a hinge motion between the Nand C-terminal domains of JNK1”
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“Despite the small size of SP600125 (molecular weight ¼ 220), it effectively occupies the hydrophobic pocket of the ATP-binding site in JNK1”
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“As a result of the high homology of sequences with 92% identity, the overall architecture of JNK1 is substantially equal to that of JNK3 (PDB entry 1JNK; Xie et al , 1998).”
What the sources say
- Not checked yetcites Xie et al , 1998 source
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“we have determined the crystal structure of JNK1 in complex with pepJIP1, the docking site peptide of JIP1 (residues 153-163), at a resolution of 2.35 A ˚ .”
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“and distorts the ATPbinding cleft”
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“Leu160 and Leu162 of the f A-Xf B motif in pepJIP1 are extensively surrounded by many hydrophobic residues of JNK1 including Met121, Val118, Leu115, Ala113, Leu123, Val59, Leu131, and Cys163”
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“Arg156 ( f A 4) interacts with Glu329 with a bidentate salt bridge of length 2.70 A ˚ .”
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“We also determined the structure of the ternary complex JNK1-pepJIP1-SP600125 at a resolution of 2.7 A ˚ .”
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“reducing the affinity of the kinase for ATP.”
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“It is the first structure demonstrating the way by which MAPKs are selectively regulated by their scaffolding proteins.”
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In the paper
“The K d values for pepJIP1 to bind to wild type, R127A, and E329A were found to be 0.42 7 0.13, 6.4 7 2.2, and 9.1 7 3.4 m M, respectively”
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In the paper
“The peptide docks to the docking groove of JNK1, a surface of the Cterminal domain covering a 2, a 3, a 13, and b 8, which is away from the ATP pocket or substrate recognition site”
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“In this structure, it is found that the docking site of the scaffolding protein also binds at the same docking grooves of JNK1 as the upstream kinase and the substrate transcription factor do in p38 MAPK (Chang et al , 2002), but with quite different interaction modes.”
What the sources say
- Not checked yetcites Chang et al , 2002 source
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In the paper
“Much more residues of the phosphorylation loop of the JNK1 complex are disordered than the JNK3 structure (missing residues 175-187 in JNK1-pepJIP1 and 212-216 in JNK3) although their ordered regions adopt a similar conformation”
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In the paper
“The most interesting result of the pepJIP1 binding to JNK1 is the rotation of the N-terminal domain relative to the Cterminal domain by approximately 15 1 , thereby distorting the ATP-binding site and inducing disorder of the phosphorylation loop”
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“The most striking feature of the present structure is the distortion of the ATP-binding site induced by the interdomain rearrangement upon pepJIP1 binding, providing another mechanism of allosteric inhibition of the kinase activity by interfering with productive binding of ATP.”
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“The hinge motion is triggered in b 8, which interacts with Leu162 ( f B) by van der Waals contacts, and is propagated to the N-terminal domain via the single loop, which connects b 7 and b 8.”
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“Fortunately, the small molecule, SP600125, occupied the deepest adenine-binding site only, not expanding to the phosphate-binding site”
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In the paper
“The most notable difference is that the f A-Xf B motif of pepJIP1, especially Leu162 ( f B), is shifted by the structural difference between JNK1 and p38 in the region containing the hydrophobic residues critical for the f A-Xf B motif binding. In this region, JNK1 forms a oneturn helix ( a 2), but a two-turn helix in p38.”
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“in the structure of the JNK1-pepJIP1 complex, the a 1 helix moved too far away for such interactions to occur as a result of the interdomain rearrangement upon pepJIP1 binding, and this loss of interactions released the phosphorylation loop of JNK1pepJIP1 from the N-terminal domain, resulting in the increased disorder of the loop.”
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In the paper
“The root-mean-square (r.m.s.) deviations for C a atoms of the Nand C-terminal domain between the structures of JNK1-pepJIP1 and JNK3 are 1.27 and 0.79 A ˚ , respectively. These values show that there is no significant structural difference between the corresponding domains.”
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In the paper
“However, the overexpression of either the domain within JIP1 that binds to JNK, or the full-length protein, potently inhibits JNK signaling in the cell (Dickens et al , 1997).”
What the sources say
- Not checked yetcites Dickens et al , 1997 source
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In the paper
“JNK-interacting protein-1 (JIP1) was identified as a scaffolding protein of the JNK module in yeast two-hybrid analysis, enhancing the correspondent signaling through the pathway (Whitmarsh et al , 1998).”
What the sources say
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In the paper
“In the structure, the INK4 inhibitors bind next to the ATP-binding site, opposite where the activating cyclin binds, and thereby not only prevent cyclin binding indirectly but also reduce the affinity of the kinase for ATP by causing extensive allosteric changes in CDK6.”
What the sources say
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This implies that JNK and p38 may act as chemomechanical energy transducers, using peptide binding energy to generate allosteric conformational changes (Goldsmith, 1996).”
What the sources say
- Not checked yetcites Goldsmith, 1996 source
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In the paper
“However, similar but nonidentical docking grooves in each MAPKs appear to be the important determinant of pathway specificity in addition to the variations in sequences of docking sites.”
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In the paper
“And the size of the pocket may also be connected with the intrinsic flexibility of the loops around the catalytic cleft in protein kinases, and the diverse modes of the flexibility dependent on each protein kinases could be important determinants of the selectivity of SP600125.”
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In the paper
“SP600125 is a reversible ATPcompetitive inhibitor with more than 20-fold selectivity over other kinases including Erk, p38 MAPKs, MKKs, and PKCs.”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
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In the paper
“Recently, the structure of JNK3 in complex with SP600125 was reported (PDB entry 1PMV; Scapin et al , 2003).”
What the sources say
- Not checked yetcites Scapin et al , 2003 source
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In the paper
“In cells, SP600125 dose-dependently inhibited the phosphorylation of c-jun, the expression of inflammatory genes COX-2, IL2, IHNg , and TNFa , and prevented the activation and differentiation of human CD4 cell.”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
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In the paper
“The latest result demonstrates that the JNK specificity of SP600125 is not so excellent and this compound inhibits some protein kinases with similar or greater potency than JNK (Bain et al , 2003).”
What the sources say
- Not checked yetcites Bain et al , 2003 source
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In the paper
“This distortion would not eliminate the ATP binding, but it would significantly reduce ATP affinity and may well disorient any bound ATP with respect to the kinase catalysis, and thus inhibit the JNK activity to phosphorylate the substrates.”
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In the paper
“the release of the phosphorylation loop, when JNK binds to the JIP1 scaffolding protein, may give a chance for the loop to refold and take an appropriate conformation to be recognized and phosphorylated by MKKs, which are also scaffolded in JIP1, and be ready to recognize the substrates.”
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In the paper
“the docking site can be characterized by not only the sequential similarity of the f A-Xf B motifs but also the conformational conservation of the motifs in their structures.”
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In the paper
“In in vivo studies in mice, SP600125 inhibited lipopolysaccharide-induced expression of TNFa and prevented anti-CD3-mediated thymocyte apoptosis (Bennett et al , 2001).”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
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In the paper
“In other words, the inhibition of the full-length JIP1 in vivo is more complicated than that of pepJIP1, and the structural feature of the inhibition by full-length JIP1 might have significant differences from that of pepJIP1.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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 docking groove of JNK1 is expected to accommodate the docking sites of MKK7 or c-jun as that of p38 does, but there may exist other important determinants than the interaction by Arg156 ( f A 4) of JIP1 for specific recognition of the docking sites of MKK7 or c-jun because this residue is not conserved in the sequential comparison (Figure 1D).”
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In the paper
“Phosphorylation of JNK by MKKs and activation of c-jun by JNK also might undergo such an interdomain rearrangement as the JNK1-pepJIP1 complex due to the intrinsic flexibility of the loops around the catalytic cleft.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“These previous studies imply that therapeutic inhibition of JNK has significant potential in inflammatory disease, acute organ failure due to apoptotic cell death, and cancer.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The fact that the N- and C-terminal domains are linked by only two loops, the loop connecting b 7 and b 8 and the disordered 331-351 loop, implies that the intrinsic flexibility may exist in the kinase, and the inherent structural flexibility may play a central role in its regulation upon JIP1 binding to JNK1.”
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It may state two separate claims as one.
The paper relies on this without support.
SP600125 has similar potency against the JNK1, JNK2, and JNK3 isoforms.
“SP600125 inhibited JNK1, 2, and 3 isoforms with similar potency”
The paper relies on this without support.
The hydrophobic residues in the adenine-binding pocket are conserved across JNK isoforms.
“all of the hydrophobic residues are conserved in JNK isoforms.”
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 check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Similarly, while both electrostatic pockets (W L, W U ) are present and occupied by different KIM peptides in ERK, p38, and FUS3, only the W L pocket is engaged by KIM peptides that bind specifically to JNKs [Fig.2(A)].”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [51]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The two docking peptides adopted different main chain conformations between the contact points corresponding to the D-motif consensus sequence.”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [13]
Experimental — accuracy not yet measuredIn the citing paper
“In contrast, only three hydrophobic pockets (U A , U B , and U L ) are present in JNKs [Fig.2(A)].46,51,52”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [51]
In the citing paper
“The structure of JNK1 bound to a peptide from JIP1 protein showed that the peptide induced a rotation of the two lobes that distorted the active site, which was proposed as a mechanism for JIP1-mediated inhibition of JNK signaling (Heo et al., 2004).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Heo et al., 2004
In the citing paper
“In the initial publication of JIP1-bound JNK (Heo et al., 2004), the interlobe rotation was apparent, but not the more substantial lobe opening, nor the mechanism of allosteric signal transduction, due to the inherent limitations of examining a single structure.”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Heo et al., 2004
In the citing paper
“At the structural level, MAPK docking is a well characterized protein-peptide interaction system (9, 12-16).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [13]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Disorder of the phosphorylation loop
“missing residues 175-187 in JNK1-pepJIP1 and 212-216 in JNK3”
§ Structure determination and refinement
“The final model contained one JNK1 molecule of residues 9-172, 190-281, 287-336, and 349-363, one pepJIP1 molecule of residues 154-163, and 97 water molecules.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Interdomain rearrangement mediated by pepJIP1 binding
“pepMEF2A (saturated red) or pepMKK3b (saturated blue) bound in p38 MAPK (whitened blue)”
§ Interdomain rearrangement mediated by pepJIP1 binding
“The residues of pepJIP1, pepMEF2A, and pepMKK7 are labeled black, red, and blue, respectively.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Interdomain rearrangement mediated by pepJIP1 binding
“And the structure of E327 of JNK1 is compared with those of the corresponding glutamates of JNK3 (green), p38 (blue), and Erk2 (pink).”
§ pepJIP1 as a JNK-specific inhibitor
“And the fact that the structure of Glu329 of JNK1 complexed with pepJIP1 is actually identical to that of Glu367 of free JNK3”
Citations
Cites
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Cited by
Sorted by citations
ERK1/2 MAP kinases: Structure, function, and regulation
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“Based upon X-ray crystallographic studies, the A-X- B sequences within D-sites bind to mouse p38 [110] and human JNK1 [111] in a hydrophobic groove flanked by helices D and E and the 7- 8 reverse turn.”
BackgroundThe JNK signal transduction pathway
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Metadata
- Authors
- Heo, Y., Kim, S., Seo, C. I., Kim, Y. K., Sung, B., Lee, H. S., Lee, J. I., Park, S., Kim, J. H., Hwang, K. Y., Hyun, Y., Jeon, Y. H., Ro, S., Cho, J. M., Lee, T. G., & Yang, C.
- Affiliations
- Seoul National University (KR)
- CrystalGenomics (South Korea) (KR)
- Yokohama City University (JP)
- Corresponding author
- Lee, Tae Gyu
- Yang, Chul‐Hak
- ORCID
- Venue
- The EMBO Journal
- Published
- 2004-05-13
- Volume
- 23
- Issue
- 11
- Pages
- 2185-2195
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC419904
- OpenAlex
- W2132108032
- Semantic Scholar
- ea6807d2e0dc42824be4ee4eab16e61e43294855
- Cited by
- 275
- References
- 46
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 10 · 2014: 14 · 2013: 17 · 2012: 21
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Korea Research Institute of Bioscience and Biotechnology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- JNK1, JIP1, SP600125, c-Jun N-terminal kinase, MAPK signaling, allosteric inhibition, kinase specificity, peptide binding, hinge motion, ternary complex structure, scaffold proteins, crystal structure
- MeSH terms
- Adenosine Triphosphate, Allosteric Regulation, Anthracenes, Arginine, Binding Sites, Calorimetry, HeLa Cells, Humans, Hydrogen Bonding, Leucine, Models, Molecular, Proline, Protein Binding, Protein Conformation, Transfection, Blotting, Western, Signal Transduction, Protein Structure, Tertiary, Crystallography, X-Ray, Glutamic Acid, Mitogen-Activated Protein Kinase 8, Adaptor Proteins, Signal Transducing
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