1jnk
From Proteopedia
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THE C-JUN N-TERMINAL KINASE (JNK3S) COMPLEXED WITH MGAMP-PNP
Contents |
Overview
BACKGROUND: The c-Jun N-terminal kinases (JNKs) are members of the, mitogen-activated protein (MAP) kinase family, and regulate signal, transduction in response to environmental stress. Activation and nuclear, localization of JNK3, a neuronal-specific isoform of JNK, has been, associated with hypoxic and ischemic damage of CA1 neurons in the, hippocampus. Knockout mice lacking JNK3 showed reduced apoptosis of, hippocampal neurons and reduced seizure induced by kainic acid, a, glutamate-receptor agonist. Thus, JNK3 may be important in the pathology, of neurological disorders and is of significant medical interest. RESULTS:, We report here the structure of unphosphorylated JNK3 in complex with, adenylyl imidodiphosphate, an ATP analog. JNK3 has a typical kinase fold, with the ATP-binding site situated within a cleft between the N- and, C-terminal domains. In contrast to other known MAP kinase structures, the, ATP-binding site of JNK3 is well ordered; the glycine-rich, nucleotide-binding sequence forms a beta-strand-turn-beta-strand structure, over the nucleotide. Unphosphorylated JNK3 assumes an open conformation, in which the N- and C-terminal domains are twisted apart relative to their, positions in cAMP-dependent protein kinase. The rotation leads to the, misalignment of some of the catalytic residues. The phosphorylation lip of, JNK3 partially blocks the substrate-binding site. CONCLUSIONS: This is the, first JNK structure to be determined, providing a unique opportunity to, compare structures from the three MAP kinase subfamilies. The structure, reveals atomic-level details of the shape of JNK3 and the interactions, between the kinase and the nucleotide. The misalignment of catalytic, residues and occlusion of the active site by the phosphorylation lip may, account for the low activity of unphosphorylated JNK3. The structure, provides a framework for understanding the substrate specificity of, different JNK isoforms, and should aid the design of selective JNK3, inhibitors.
Disease
Known diseases associated with this structure: Epileptic encephalopathy, Lennox-Gastaut type OMIM:[602897]
About this Structure
1JNK is a Single protein structure of sequence from Homo sapiens with MG and ANP as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of JNK3: a kinase implicated in neuronal apoptosis., Xie X, Gu Y, Fox T, Coll JT, Fleming MA, Markland W, Caron PR, Wilson KP, Su MS, Structure. 1998 Aug 15;6(8):983-91. PMID:9739089
Page seeded by OCA on Mon Nov 12 17:42:47 2007
