7M0X

Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and PD0325901

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7M0X の概要

• エントリーDOI: 10.2210/pdb7m0x/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, Dual specificity mitogen-activated protein kinase kinase 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (9 entities in total)
• 機能のキーワード: braf, mek1, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77843.35

構造登録者

Li, K.,Gonzalez Del-Pino, G.,Ha, B.H.,Park, E.,Eck, M.J. (登録日: 2021-03-11, 公開日: 2021-04-21, 最終更新日: 2023-10-18)

主引用文献

Gonzalez-Del Pino, G.L.,Li, K.,Park, E.,Schmoker, A.M.,Ha, B.H.,Eck, M.J.
Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: The RAF/MEK/ERK pathway is central to the control of cell physiology, and its dysregulation is associated with many cancers. Accordingly, the proteins constituting this pathway, including MEK1/2 (MEK), have been subject to intense drug discovery and development efforts. Allosteric MEK inhibitors (MEKi) exert complex effects on RAF/MEK/ERK pathway signaling and are employed clinically in combination with BRAF inhibitors in malignant melanoma. Although mechanisms and structures of MEKi bound to MEK have been described for many of these compounds, recent studies suggest that RAF/MEK complexes, rather than free MEK, should be evaluated as the target of MEKi. Here, we describe structural and biochemical studies of eight structurally diverse, clinical-stage MEKi to better understand their mechanism of action on BRAF/MEK complexes. We find that all of these agents bind in the MEK allosteric site in BRAF/MEK complexes, in which they stabilize the MEK activation loop in a conformation that is resistant to BRAF-mediated dual phosphorylation required for full activation of MEK. We also show that allosteric MEK inhibitors act most potently on BRAF/MEK complexes rather than on free active MEK, further supporting the notion that a BRAF/MEK complex is the physiologically relevant pharmacologic target for this class of compounds. Our findings provide a conceptual and structural framework for rational development of RAF-selective MEK inhibitors as an avenue to more effective and better-tolerated agents targeting this pathway.

PubMed: 34470822
DOI: 10.1073/pnas.2107207118

実験手法

X-RAY DIFFRACTION (2.47 Å)