Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation

Nat Struct Mol Biol. 2015 Jan;22(1):37-43. doi: 10.1038/nsmb.2924. Epub 2014 Dec 1.


Reported RAF kinase domain structures adopt a side-to-side dimer configuration reflective of an 'on' state that underpins an allosteric mechanism of regulation. Atomic details of the monomer 'off' state have been elusive. Reinspection of the BRAF kinase domain structures revealed that sulfonamide inhibitors induce features of an off state, primarily a laterally displaced helix αC stabilized by the activation segment helix 1 (AS-H1). These features correlated with the ability of sulfonamides to disrupt human BRAF homodimers in cells, in vitro and in crystals yielding a structure of BRAF in a monomer state. The crystal structure revealed exaggerated, nonproductive positions of helix αC and AS-H1, the latter of which is the target of potent BRAF oncogenic mutations. Together, this work provides formal proof of an allosteric link between the RAF dimer interface, the activation segment and the catalytic infrastructure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Humans
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization / drug effects
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / chemistry*
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Sulfonamides / metabolism


  • Sulfonamides
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Associated data

  • PDB/4WO5