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Structure paper

TitleBRAF oncogenic mutants evade autoinhibition through a common mechanism.
Journal, issue, pagesScience, Vol. 388, Issue 6750, Page eadp2742, Year 2025
Publish dateMay 29, 2025
AuthorsHugo Lavoie / Ting Jin / Driss Lajoie / Marion Decossas / Patrick Gendron / Bing Wang / Frantisek Filandr / Malha Sahmi / Chang Hwa Jo / Sandra Weber / Geneviève Arseneault / Sasmita Tripathy / Pierre Beaulieu / Doris A Schuetz / David C Schriemer / Anne Marinier / William J Rice / Pierre Maisonneuve / Marc Therrien /
PubMed AbstractUncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving ...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.
External linksScience / PubMed:40440367
MethodsEM (single particle)
Resolution3.06 - 5.86 Å
Structure data

43673

8vyo

EMDB-43673, PDB-8vyo:
Cryo-EM Structure of the BRAF WT monomer
Method: EM (single particle) / Resolution: 3.74 Å

43674

8vyp

EMDB-43674, PDB-8vyp:
Cryo-EM Structure of the BRAF V600E monomer
Method: EM (single particle) / Resolution: 3.29 Å

43675

8vyq

EMDB-43675, PDB-8vyq:
Cryo-EM Structure of the BRAF V600K monomer
Method: EM (single particle) / Resolution: 4.43 Å

43676

8vyr

EMDB-43676, PDB-8vyr:
Cryo-EM Structure of the BRAF V600E monomer bound to GDC0879
Method: EM (single particle) / Resolution: 4.32 Å

43677

8vys

EMDB-43677, PDB-8vys:
Cryo-EM Structure of the BRAF V600E monomer bound to PLX8394
Method: EM (single particle) / Resolution: 3.06 Å

43678

8vyu

EMDB-43678, PDB-8vyu:
Cryo-EM Structure of the BRAF WT monomer bound to PLX8394
Method: EM (single particle) / Resolution: 4.07 Å

43679

8vyv

EMDB-43679, PDB-8vyv:
Cryo-EM Structure of the BRAF K601E monomer
Method: EM (single particle) / Resolution: 5.86 Å

43680

8vyw

EMDB-43680, PDB-8vyw:
Cryo-EM Structure of the BRAF D594G monomer
Method: EM (single particle) / Resolution: 4.76 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

PDB-1aen:
SPECIFICITY OF LIGAND BINDING TO A BURIED POLAR CAVITY AT THE ACTIVE SITE OF CYTOCHROME C PEROXIDASE (2-AMINO-5-METHYLTHIAZOLE)

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/INHIBITOR / BRAF Kinase Monomer / TRANSFERASE-INHIBITOR complex / BRAF Kinase Oncogenic Mutant Monomer / BRAF Kinase Monomer Mutant Inhibitor / BRAF Kinase Monomer Inhibitor

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