The DOI matches its Crossref record; 44 of the 47 references it cites were found in a registry or an index.
The Structure of JNK3 in Complex with Small Molecule Inhibitors
Open accessAbstract
The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“Recently, the structure of JNK3 in complex with SP600125 was reported (PDB entry 1PMV; Scapin et al , 2003).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Scapin et al , 2003
Citations
Cites
[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
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,616
Mammalian MAP kinase signalling cascades
Chang, L., & Karin, M. (2001) · Nature · doi:10.1038/35065000 · Cited by 5,118
AMoRe: an automated package for molecular replacement
Navaza, J. (1994) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767393007597 · Cited by 4,941
Flack, H. D., Párkányi, L., & Simon, K. (1993) · doi:10.1093/oso/9780198557883.001.0001 · Cited by 2,003
Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
Schindler, T. H., Bornmann, W. G., Pellicena, P., Miller, W. T., Clarkson, B., & Kuriyan, J. (2000) · Science · doi:10.1126/science.289.5486.1938 · Cited by 1,785
Selective interaction of JNK protein kinase isoforms with transcription factors.
Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Dérijard, B., & Davis, R. J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00636.x · Cited by 1,341
Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene
Yang, D. D., Kuan, C.-Y., Whitmarsh, A. J., Rinócn, M., Zheng, T. S., Davis, R. J., RAKIC, P. T., & Flavell, R. A. (1997) · Nature · doi:10.1038/39899 · Cited by 1,230
Mohammadi, M., McMahon, G., Sun, L., Tang, C., Hirth, P., Yeh, B. K., Hubbard, S. R., & Schlessinger, J. (1997) · Science · doi:10.1126/science.276.5314.955 · Cited by 1,099
Estus, S., Zaks, W. J., Freeman, R. S., Gruda, M. C., Bravo, R., & Johnson, E. M. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.127.6.1717 · Cited by 820
Han, Z., Boyle, D. L., Chang, L., Bennett, B. L., Karin, M., Yang, L., Manning, A. M., & Firestein, G. S. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12466 · Cited by 797
A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death
Ham, J., Babij, C., Whitfield, J. R., Pfarr, C. M., Lallemand, D., Yaniv, M., & Rubin, L. L. (1995) · Neuron · doi:10.1016/0896-6273(95)90331-3 · Cited by 795
Kallunki, T., Su, B., Tsigelny, I., Sluss, H. K., Dérijard, B., Moore, G., Davis, R., & Karin, M. (1994) · Genes & Development · doi:10.1101/gad.8.24.2996 · Cited by 642
Carson, M. (1997) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(97)77027-7 · Cited by 510
[10] Electron-density map interpretation
Jones, T. A., & Kjeldgaard, M. (1997) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(97)77012-5 · Cited by 507
Structural basis of inhibitor selectivity in MAP kinases
Wang, Z., Canagarajah, B. J., Boehm, J. C., Kassisà, S., Cobb, M. H., Young, P. R., Abdel‐Meguid, S. S., Adams, J. L., & Goldsmith, E. J. (1998) · Structure · doi:10.1016/s0969-2126(98)00113-0 · Cited by 429
Rice, L. M., & Brünger, A. T. (1994) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.340190403 · Cited by 369
Chemical Inhibitors of Protein Kinases
Bridges, A. J. (2001) · Chemical Reviews · doi:10.1021/cr000250y · Cited by 324
Eyers, P. A., Craxton, M., Morricel, N., Cohen, P., & Goedert, M. (1998) · Chemistry & Biology · doi:10.1016/s1074-5521(98)90170-3 · Cited by 310
The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase
Wilson, K. P., McCaffrey, P. G., Hsiao, K., Pazhanisamy, S., Galullo, V., Bemis, G. W., Fitzgibbon, M. J., Caron, P. R., Murcko, M. A., & Su, M. S. S. (1997) · Chemistry & Biology · doi:10.1016/s1074-5521(97)90194-0 · Cited by 275
Saporito, M. S., Brown, E. M., Miller, M. S., & Carswell, S. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37972-8 · Cited by 266
Zhu, X., Kim, J. L., Newcomb, J. R., Rose, P., Stover, D. R., Toledo, L. M., Zhao, H., & Morgenstern, K. A. (1999) · Structure · doi:10.1016/s0969-2126(99)80086-0 · Cited by 257
Xia, X., Harding, T. A., Weller, M., Bieneman, A., Uney, J. B., & Schulz, J. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181182298 · Cited by 230
p493F12 kinase: A novel MAP kinase expressed in a subset of neurons in the human nervous system
Mohit, A. A., Martin, J. H., & Miller, C. A. (1995) · Neuron · doi:10.1016/0896-6273(95)90241-4 · Cited by 206
Crystal structure of JNK3: a kinase implicated in neuronal apoptosis
Xie, X., Gu, Y., Fox, T., Coll, J. T., Fleming, M. A., Markland, W., Caron, P. R., Wilson, K. P., & Su, M. S.-S. (1998) · Structure · doi:10.1016/s0969-2126(98)00100-2 · Cited by 198
Liverton, N. J., Butcher, J. W., Claiborne, C. F., Claremon, D. A., Libby, B. E., Nguyen, K. T., Pitzenberger, S. M., Selnick, H. G., Smith, G. R., Tebben, A. J., et al. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm9805236 · Cited by 197
Mechanism-based design of a protein kinase inhibitor.
Hubbard, S. R., Cole, P. A., Parang, K., Till, J. H., Ablooglu, A. J., & Kohanski, R. A. (2001) · Nature Structural Biology · doi:10.1038/83028 · Cited by 192
Maroney, A. C., Finn, J. P., Bozyczko‐Coyne, D., O’Kane, T. M., Neff, N. T., Tolkovsky, A. M., Park, D. S., Yan, C. Y. I., Troy, C. M., & Greene, L. A. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.01901.x · Cited by 190
Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity
Fitzgerald, C. E., Patel, S. B., Becker, J. W., Cameron, P. M., Zaller, D. M., Pikounis, V. B., O’Keefe, S. J., & Scapin, G. (2003) · Nature Structural & Molecular Biology · doi:10.1038/nsb949 · Cited by 182
Self-citationThe Structure-Based Design of ATP-Site Directed Protein Kinase Inhibitors
Toledo, L. M., LYDON, N. B., & Elbaum, D. (1999) · Current Medicinal Chemistry · doi:10.2174/092986730609220401150028 · Cited by 177
Developmental expression in the mouse nervous system of the p493F12 SAP kinase
Martin, J. H., Mohit, A. A., & Miller, C. A. (1996) · Molecular Brain Research · doi:10.1016/0169-328x(95)00181-q · Cited by 137
Structural biology in drug design: selective protein kinase inhibitors
Scapin, G. (2002) · Drug Discovery Today · doi:10.1016/s1359-6446(02)02290-0 · Cited by 109
Self-citationStructure-based design of cyclin-dependent kinase inhibitors
Davies, T. G., Pratt, D. J., Endicott, J., Johnson, L. N., & Noble, M. E. M. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00182-1 · Cited by 97
Molecular Basis for p38 Protein Kinase Inhibitor Specificity
Lisnock, J., Tebben, A., Frantz, B., O’Neill, E. A., Croft, G. F., O’Keefe, S. J., Li, B., Hacker, C., de Laszlo, S. E., Smith, A. J., et al. (1998) · Biochemistry · doi:10.1021/bi981591x · Cited by 95
Self-citationBoehm, J. C., & Adams, J. L. (2000) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.10.1.25 · Cited by 80
Lisnock, J., Griffin, P., Calaycay, J., Frantz, B., Parsons, J., O'Keefe, S. J., & LoGrasso, P. (2000) · Biochemistry · doi:10.1021/bi992410+ · Cited by 79
Self-citationProtein kinase inhibitors: emerging pharmacophores 1997 - 2000
Dumas, J. (2001) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.11.3.405 · Cited by 71
Protein kinase inhibitors: structural determinants for target specificity.
McMahon, G., Sun, L., Liang, C., & Tang, C. (1998) · PubMed · Cited by 32
Inhibitors of the JNK signaling pathway
Harper, S. J., & Lo Grasso, P. (2001) · Drugs of the Future · doi:10.1358/dof.2001.026.10.858715 · Cited by 13
Self-citationProtein kinase antagonists: interim challenges and issues.
Ea, S. (2000) · PubMed · Cited by 11
Kleemann, A. (2014) · Ullmann's Encyclopedia of Industrial Chemistry · doi:10.1002/14356007.r22_r01 · Cited by 2
Laurence, A. D. J., Gadina, M., Schwartzberg, P. L., & O’Shea, J. J. (2023) · Elsevier eBooks · doi:10.1016/b978-0-7020-8165-1.00085-x · Cited by 1
Rinehart (2000) · doi:10.1002/(sici)1098-1128(200001)20:1
Cited by
Sorted by citations
Diverse, High-Quality Test Set for the Validation of Protein−Ligand Docking Performance
Hartshorn, M. J., Verdonk, M. L., Chessari, G., Brewerton, S. C., Mooij, W. T. M., Mortenson, P. N., & Murray, C. W. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm061277y · Cited by 639
Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases
Bogoyevitch, M. A., & Kobe, B. (2006) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00025-06 · Cited by 584
Halogen Bonding—A Novel Interaction for Rational Drug Design?
Lu, Y., Shi, T., Wang, Y., Yang, H., Yan, X., Luo, X., Jiang, H., & Zhu, W. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm9000133 · Cited by 562
Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation
Zuccotto, F., Ardini, E., Casale, E., & Angiolini, M. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901443h · Cited by 560
c-Jun N-terminal kinase (JNK) signaling: Recent advances and challenges
Bogoyevitch, M. A., Ngoei, K. R. W., Zhao, T. T., Yeap, Y. Y. C., & Ng, D. C. H. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.11.002 · Cited by 335
Metadata
- Authors
- Scapin, G., Patel, S. B., Lisnock, J., Becker, J. W., & LoGrasso, P. V.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Scapin, Giovanna
- ORCID
- Scapin, Giovanna
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 10
- Issue
- 8
- Pages
- 705-712
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W1891159913
- Cited by
- 131
- References
- 47
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 7 · 2019: 2 · 2018: 3 · 2016: 7 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 6
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Structural Biology › Enzyme Structure and Function
- Keywords
- JNK3, c-Jun N-terminal kinase, mitogen-activated protein kinase, kinase inhibitors, small molecule inhibitors, binding mode, kinase selectivity, structure-based drug design, neurological disorders, neuroprotection
- MeSH terms
- Adenosine Triphosphate, Binding Sites, Enzyme Inhibitors, Models, Molecular, Protein Conformation, Protein-Tyrosine Kinases, Recombinant Proteins, Structure-Activity Relationship, Crystallography, X-Ray, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 10
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.
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