| Structural highlights
4izy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 4hyu, 4hys |
| Gene: | MAPK8, hCG_23734 (HUMAN) |
| Activity: | Transferase, with EC number 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[JIP1_HUMAN] Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.[1]
Function
[JIP1_HUMAN] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
Publication Abstract from PubMed
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.,Gong L, Han X, Silva T, Tan YC, Goyal B, Tivitmahaisoon P, Trejo A, Palmer W, Hogg H, Jahagir A, Alam M, Wagner P, Stein K, Filonova L, Loe B, Makra F, Rotstein D, Rapatova L, Dunn J, Zuo F, Dal Porto J, Wong B, Jin S, Chang A, Tran P, Hsieh G, Niu L, Shao A, Reuter D, Hermann J, Kuglstatter A, Goldstein D Bioorg Med Chem Lett. 2013 Jun 15;23(12):3565-9. doi: 10.1016/j.bmcl.2013.04.029., Epub 2013 Apr 21. PMID:23664880[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH, Vionnet N, Nicod P, Boutin P, Froguel P. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet. 2000 Mar;24(3):291-5. PMID:10700186 doi:10.1038/73523
- ↑ Gong L, Han X, Silva T, Tan YC, Goyal B, Tivitmahaisoon P, Trejo A, Palmer W, Hogg H, Jahagir A, Alam M, Wagner P, Stein K, Filonova L, Loe B, Makra F, Rotstein D, Rapatova L, Dunn J, Zuo F, Dal Porto J, Wong B, Jin S, Chang A, Tran P, Hsieh G, Niu L, Shao A, Reuter D, Hermann J, Kuglstatter A, Goldstein D. Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties. Bioorg Med Chem Lett. 2013 Jun 15;23(12):3565-9. doi: 10.1016/j.bmcl.2013.04.029., Epub 2013 Apr 21. PMID:23664880 doi:http://dx.doi.org/10.1016/j.bmcl.2013.04.029
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