8VYV

Cryo-EM Structure of the BRAF K601E monomer

8VYV の概要

• エントリーDOI: 10.2210/pdb8vyv/pdb
• EMDBエントリー: 43679
• 分子名称: 14-3-3 protein zeta/delta, Serine/threonine-protein kinase B-raf (2 entities in total)
• 機能のキーワード: braf kinase oncogenic mutant monomer, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 140308.86

構造登録者

Lavoie, H.,Lajoie, D.,Jin, T.,Decossas, M.,Maisonneuve, P.,Therrien, M. (登録日: 2024-02-09, 公開日: 2025-05-28, 最終更新日: 2025-06-25)

主引用文献

Lavoie, H.,Jin, T.,Lajoie, D.,Decossas, M.,Gendron, P.,Wang, B.,Filandr, F.,Sahmi, M.,Hwa Jo, C.,Weber, S.,Arseneault, G.,Tripathy, S.,Beaulieu, P.,Schuetz, D.A.,Schriemer, D.C.,Marinier, A.,Rice, W.J.,Maisonneuve, P.,Therrien, M.
BRAF oncogenic mutants evade autoinhibition through a common mechanism.
Science, 388:eadp2742-eadp2742, 2025

PubMed Abstract: Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving monomeric autoinhibition and activation by dimerization, has been intensely scrutinized, but mechanisms enabling oncogenic mutants to evade regulation remain unclear. By using cryo-electron microscopy, we solved the three-dimensional structures of the three oncogenic BRAF mutant classes, including the common V600E variant. These mutations disrupted wild-type BRAF's autoinhibited state, mediated by interactions between the cysteine-rich domain and kinase domain, thereby shifting the kinase domain into a preactivated conformation. This structural change likely results from helix αC displacement. PLX8394, a BRAF inhibitor that stabilizes helix αC in an inactive conformation, restored the autoinhibited conformation of oncogenic BRAF, explaining the properties of this class of compounds.

PubMed: 40440367
DOI: 10.1126/science.adp2742

実験手法

ELECTRON MICROSCOPY (5.86 Å)