8VYW

Cryo-EM Structure of the BRAF D594G monomer

Summary for 8VYW

• Entry DOI: 10.2210/pdb8vyw/pdb
• EMDB information: 43680
• Descriptor: 14-3-3 protein zeta/delta, Serine/threonine-protein kinase B-raf (2 entities in total)
• Functional Keywords: braf kinase oncogenic mutant monomer, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 97746.20

Authors

Lavoie, H.,Lajoie, D.,Jin, T.,Decossas, M.,Maisonneuve, P.,Therrien, M. (deposition date: 2024-02-09, release date: 2025-05-28, Last modification date: 2025-06-25)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (4.76 Å)