3WIG

Human MEK1 kinase in complex with CH5126766 and MgAMP-PNP

3WIG の概要

• エントリーDOI: 10.2210/pdb3wig/pdb
• 関連するPDBエントリー: 3ORN 3OS3
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: kinase, kinase inhibitor, allosteric, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35612.89

構造登録者

Lukacs, C.M.,Janson, C.,Schuck, V. (登録日: 2013-09-12, 公開日: 2014-06-04, 最終更新日: 2024-03-20)

主引用文献

Lito, P.,Saborowski, A.,Yue, J.,Solomon, M.,Joseph, E.,Gadal, S.,Saborowski, M.,Kastenhuber, E.,Fellmann, C.,Ohara, K.,Morikami, K.,Miura, T.,Lukacs, C.,Ishii, N.,Lowe, S.,Rosen, N.
Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors
Cancer Cell, 25:697-710, 2014

PubMed Abstract: MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

PubMed: 24746704
DOI: 10.1016/j.ccr.2014.03.011

実験手法

X-RAY DIFFRACTION (2.7 Å)