2FSM

mitogen activated protein kinase p38alpha (D176A+F327S) activating mutant form-B

2FSM の概要

• エントリーDOI: 10.2210/pdb2fsm/pdb
• 関連するPDBエントリー: 2FSL 2FSO 2FST
• 分子名称: Mitogen-activated protein kinase 14, octyl beta-D-glucopyranoside (3 entities in total)
• 機能のキーワード: mitogen activated protein kinase, p38, active mutants, lipids, map kinase insertion, autophosphorylation, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42431.42

構造登録者

Diskin, R.,Livnah, O. (登録日: 2006-01-23, 公開日: 2006-12-05, 最終更新日: 2024-05-29)

主引用文献

Diskin, R.,Lebendiker, M.,Engelberg, D.,Livnah, O.
Structures of p38alpha Active Mutants Reveal Conformational Changes in L16 Loop that Induce Autophosphorylation and Activation
J.Mol.Biol., 365:66-76, 2007

PubMed Abstract: p38 mitogen-activated protein (MAP) kinases function in numerous signaling processes and are crucial for normal functions of cells and organisms. Abnormal p38 activity is associated with inflammatory diseases and cancers making the understanding of its activation mechanisms highly important. p38s are commonly activated by phosphorylation, catalyzed by MAP kinase kinases (MKKs). Moreover, it was recently revealed that the p38alpha is also activated via alternative pathways, which are MKK independent. The structural basis of p38 activation, especially in the alternative pathways, is mostly unknown. This lack of structural data hinders the study of p38's biology as well as the development of novel strategies for p38 inhibition. We have recently discovered and optimized a novel set of intrinsically active p38 mutants whose activities are independent of any upstream activation. The high-resolution crystal structures of the intrinsically active p38alpha mutants reveal that local alterations in the L16 loop region promote kinase activation. The L16 loop can be thus regarded as a molecular switch that upon conformational changes promotes activation. We suggest that similar conformational changes in L16 loop also occur in natural activation mechanisms of p38alpha in T-cells. Our biochemical studies reveal novel mechanistic insights into the activation process of p38. In this regard, the results indicate that the activation mechanism of the mutants involves dimerization and subsequent trans autophosphorylation on Thr180 (on the phosphorylation lip). Finally, we suggest a model of in vivo p38alpha activation induced by the L16 switch with auto regulatory characteristics.

PubMed: 17059827
DOI: 10.1016/j.jmb.2006.08.043

実験手法

X-RAY DIFFRACTION (1.86 Å)