1KV2

Human p38 MAP Kinase in Complex with BIRB 796

1KV2 の概要

• エントリーDOI: 10.2210/pdb1kv2/pdb
• 関連するPDBエントリー: 1IAN 1KV1
• 分子名称: p38 MAP kinase, 1-(5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL)-3-[4-(2-MORPHOLIN-4-YL-ETHOXY)-NAPHTHALEN-1-YL]-UREA (2 entities in total)
• 機能のキーワード: protein-inhibitor complex, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41870.85

構造登録者

Pargellis, C.,Tong, L.,Churchill, L.,Cirillo, P.F.,Gilmore, T.,Graham, A.G.,Grob, P.M.,Hickey, E.R.,Moss, N.,Pav, S.,Regan, J. (登録日: 2002-01-23, 公開日: 2002-03-27, 最終更新日: 2024-02-14)

主引用文献

Pargellis, C.,Tong, L.,Churchill, L.,Cirillo, P.F.,Gilmore, T.,Graham, A.G.,Grob, P.M.,Hickey, E.R.,Moss, N.,Pav, S.,Regan, J.
Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site.
Nat.Struct.Biol., 9:268-272, 2002

PubMed Abstract: The p38 MAP kinase plays a crucial role in regulating the production of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. Blocking this kinase may offer an effective therapy for treating many inflammatory diseases. Here we report a new allosteric binding site for a diaryl urea class of highly potent and selective inhibitors against human p38 MAP kinase. The formation of this binding site requires a large conformational change not observed previously for any of the protein Ser/Thr kinases. This change is in the highly conserved Asp-Phe-Gly motif within the active site of the kinase. Solution studies demonstrate that this class of compounds has slow binding kinetics, consistent with the requirement for conformational change. Improving interactions in this allosteric pocket, as well as establishing binding interactions in the ATP pocket, enhanced the affinity of the inhibitors by 12,000-fold. One of the most potent compounds in this series, BIRB 796, has picomolar affinity for the kinase and low nanomolar inhibitory activity in cell culture.

PubMed: 11896401
DOI: 10.1038/nsb770

実験手法

X-RAY DIFFRACTION (2.8 Å)