4E6C

p38a-perifosine Complex

4E6C の概要

• エントリーDOI: 10.2210/pdb4e6c/pdb
• 関連するPDBエントリー: 1P38 2NPQ 4E5A 4E5B 4E6A 4E8A
• 分子名称: Mitogen-activated protein kinase 14, (1,1-dimethylpiperidin-1-ium-4-yl) octadecyl hydrogen phosphate (3 entities in total)
• 機能のキーワード: map kinase, p38, signal transduction, alternative activation modes, lipid binding site, pia, perifosine, kinase fold, kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41805.86

構造登録者

Livnah, O.,Tzarum, N.,Eisenberg-Domovich, Y. (登録日: 2012-03-15, 公開日: 2012-10-31, 最終更新日: 2024-02-28)

主引用文献

Tzarum, N.,Eisenberg-Domovich, Y.,Gills, J.J.,Dennis, P.A.,Livnah, O.
Lipid Molecules Induce p38 alpha Activation via a Novel Molecular Switch.
J.Mol.Biol., 424:339-353, 2012

PubMed Abstract: p38α mitogen-activated protein kinase (MAPK) is generally activated by dual phosphorylation but has also been shown to exhibit alternative activation modes. One of these modes included a direct interaction with phosphatidylinositol ether lipid analogues (PIA) inducing p38α autoactivation and apoptosis. Perifosine, an Akt inhibitor in phase II clinical trials, also showed p38α activation properties similarly to those of PIAs. The crystal structures of p38α in complex with PIA23, PIA24 and perifosine provide insights into this unique activation mode. The activating molecules bind a unique hydrophobic binding site in the kinase C'-lobe formed in part by the MAPK insert region. In addition, there are conformational changes in the short αEF/αF loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the αEF/αF loop identified Trp197 as a key residue in the lipid binding and in p38α catalytic activity. The lipid binding site also accommodates hydrophobic inhibitor molecules and, thus, can serve as a novel p38α-target for specific activation or inhibition, with novel therapeutic implications.

PubMed: 23079240
DOI: 10.1016/j.jmb.2012.10.007

実験手法

X-RAY DIFFRACTION (2.39 Å)