4LOO

Structural basis of autoactivation of p38 alpha induced by TAB1 (Monoclinic crystal form)

4LOO の概要

• エントリーDOI: 10.2210/pdb4loo/pdb
• 分子名称: Mitogen-activated protein kinase 14, TGF-beta-activated kinase 1 and MAP3K7-binding protein 1, 4-(4-FLUOROPHENYL)-1-(4-PIPERIDINYL)-5-(2-AMINO-4-PYRIMIDINYL)-IMIDAZOLE, ... (4 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, protein kinase, kinase-regulatory protein complex, mapk, autoactivation, autophosphorylation, transferase
• 由来する生物種: Mus musculus (mouse); 詳細
• 細胞内の位置: Cytoplasm: P47811
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44836.11

構造登録者

Chaikuad, A.,DeNicola, G.F.,Krojer, T.,Allerston, C.K.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Marber, M.S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2013-07-13, 公開日: 2013-08-21, 最終更新日: 2023-09-20)

主引用文献

De Nicola, G.F.,Martin, E.D.,Chaikuad, A.,Bassi, R.,Clark, J.,Martino, L.,Verma, S.,Sicard, P.,Tata, R.,Atkinson, R.A.,Knapp, S.,Conte, M.R.,Marber, M.S.
Mechanism and consequence of the autoactivation of p38 alpha mitogen-activated protein kinase promoted by TAB1.
Nat.Struct.Mol.Biol., 20:1182-1190, 2013

PubMed Abstract: p38α mitogen-activated protein kinase (p38α) is activated by a variety of mechanisms, including autophosphorylation initiated by TGFβ-activated kinase 1 binding protein 1 (TAB1) during myocardial ischemia and other stresses. Chemical-genetic approaches and coexpression in mammalian, bacterial and cell-free systems revealed that mouse p38α autophosphorylation occurs in cis by direct interaction with TAB1(371-416). In isolated rat cardiac myocytes and perfused mouse hearts, TAT-TAB1(371-416) rapidly activates p38 and profoundly perturbs function. Crystal structures and characterization in solution revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe. TAB1 binding stabilizes active p38α and induces rearrangements within the activation segment by helical extension of the Thr-Gly-Tyr motif, allowing autophosphorylation in cis. Interference with p38α recognition by TAB1 abolishes its cardiac toxicity. Such intervention could potentially circumvent the drawbacks of clinical pharmacological inhibitors of p38 catalytic activity.

PubMed: 24037507
DOI: 10.1038/nsmb.2668

実験手法

X-RAY DIFFRACTION (1.95 Å)