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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.
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“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
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BindingDB Entry 50031494: Small molecule JNK (c-Jun N-terminal kinase) inhibitors.
BindingDB (2010) · UC San Diego · doi:10.7270/q2ks6rp5
BindingDB Entry 50028628: Halogen bonding--a novel interaction for rational drug design?
BindingDB (2010) · UC San Diego · doi:10.7270/q2xw4jp2
BindingDB Entry 2911: Biphenyl amide p38 kinase inhibitors 1: Discovery and binding mode.
BindingDB (2008) · UC San Diego · doi:10.7270/q2kp80g3
BindingDB Entry 50041788: 1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3.
BindingDB (2013) · UC San Diego · doi:10.7270/q2z320wr
BindingDB (2009) · UC San Diego · doi:10.7270/q208652m
BindingDB Entry 50045381: Inhibitors of c-Jun N-terminal kinases: an update.
BindingDB (2016) · UC San Diego · doi:10.7270/q2jh3nvz
BindingDB Entry 50021380: 3,5-Disubstituted quinolines as novel c-Jun N-terminal kinase inhibitors.
BindingDB (2009) · UC San Diego · doi:10.7270/q26m36kx
BindingDB (2009) · UC San Diego · doi:10.7270/q2959h7w
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
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