6U2G

BRAF-MEK complex with AMP-PCP bound to BRAF

6U2G の概要

• エントリーDOI: 10.2210/pdb6u2g/pdb
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, Serine/threonine-protein kinase B-raf, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: kinase, amp-pcp, dimer, signaling protei, 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: 79879.59

構造登録者

Liau, N.P.D.,Wendorff, T.,Hymowitz, S.,Sudhamsu, J. (登録日: 2019-08-19, 公開日: 2019-08-28, 最終更新日: 2023-10-11)

主引用文献

Liau, N.P.D.,Wendorff, T.J.,Quinn, J.G.,Steffek, M.,Phung, W.,Liu, P.,Tang, J.,Irudayanathan, F.J.,Izadi, S.,Shaw, A.S.,Malek, S.,Hymowitz, S.G.,Sudhamsu, J.
Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization.
Nat.Struct.Mol.Biol., 27:134-141, 2020

PubMed Abstract: The RAS-RAF-MEK-ERK signaling axis is frequently activated in human cancers. Physiological concentrations of ATP prevent formation of RAF kinase-domain (RAF) dimers that are critical for activity. Here we present a 2.9-Å-resolution crystal structure of human BRAF in complex with MEK and the ATP analog AMP-PCP, revealing interactions between BRAF and ATP that induce an inactive, monomeric conformation of BRAF. We also determine how 14-3-3 relieves the negative regulatory effect of ATP through a 2.5-Å-resolution crystal structure of the BRAF-14-3-3 complex, in which dimeric 14-3-3 enforces a dimeric BRAF assembly to increase BRAF activity. Our data suggest that most oncogenic BRAF mutations alter interactions with ATP and counteract the negative effects of ATP binding by lowering the threshold for RAF dimerization and pathway activation. Our study establishes a framework for rationalizing oncogenic BRAF mutations and provides new avenues for improved RAF-inhibitor discovery.

PubMed: 31988522
DOI: 10.1038/s41594-019-0365-0

実験手法

X-RAY DIFFRACTION (2.886 Å)