3ttj

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3ttj, resolution 2.10Å ()
Ligands:
Gene: MAPK10, JNK3, JNK3A, PRKM10 (Homo sapiens)
Activity: Mitogen-activated protein kinase, with EC number 2.7.11.24
Related: 3tti


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal Structure of JNK3 complexed with CC-359, a JNK inhibitor for the prevention of ischemia-reperfusion injury

Publication Abstract from PubMed

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury., Krenitsky VP, Delgado M, Nadolny L, Sahasrabudhe K, Ayala L, Clareen SS, Hilgraf R, Albers R, Kois A, Hughes K, Wright J, Nowakowski J, Sudbeck E, Ghosh S, Bahmanyar S, Chamberlain P, Muir J, Cathers BE, Giegel D, Xu L, Celeridad M, Moghaddam M, Khatsenko O, Omholt P, Katz J, Pai S, Fan R, Tang Y, Shirley MA, Benish B, Blease K, Raymon H, Bhagwat S, Henderson I, Cole AG, Bennett B, Satoh Y, Bioorg Med Chem Lett. 2011 Dec 11. PMID:22226655

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation.

Function

[MK10_HUMAN] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1]

About this Structure

3ttj is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Krenitsky VP, Delgado M, Nadolny L, Sahasrabudhe K, Ayala L, Clareen SS, Hilgraf R, Albers R, Kois A, Hughes K, Wright J, Nowakowski J, Sudbeck E, Ghosh S, Bahmanyar S, Chamberlain P, Muir J, Cathers BE, Giegel D, Xu L, Celeridad M, Moghaddam M, Khatsenko O, Omholt P, Katz J, Pai S, Fan R, Tang Y, Shirley MA, Benish B, Blease K, Raymon H, Bhagwat S, Henderson I, Cole AG, Bennett B, Satoh Y. Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury. Bioorg Med Chem Lett. 2011 Dec 11. PMID:22226655 doi:10.1016/j.bmcl.2011.12.028
  1. Neidhart S, Antonsson B, Gillieron C, Vilbois F, Grenningloh G, Arkinstall S. c-Jun N-terminal kinase-3 (JNK3)/stress-activated protein kinase-beta (SAPKbeta) binds and phosphorylates the neuronal microtubule regulator SCG10. FEBS Lett. 2001 Nov 16;508(2):259-64. PMID:11718727

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