4WO5

Crystal structure of a BRAF kinase domain monomer

Summary for 4WO5

• Entry DOI: 10.2210/pdb4wo5/pdb
• Related: 3C4C
• Descriptor: Serine/threonine-protein kinase B-raf, N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide (3 entities in total)
• Functional Keywords: kinase, monomer, inhibitor, complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 2
• Total formula weight: 69061.48

Authors

Critton, D.A. (deposition date: 2014-10-15, release date: 2014-12-03, Last modification date: 2023-09-27)

Primary citation

Thevakumaran, N.,Lavoie, H.,Critton, D.A.,Tebben, A.,Marinier, A.,Sicheri, F.,Therrien, M.
Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation.
Nat.Struct.Mol.Biol., 22:37-43, 2015

PubMed Abstract: 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.

PubMed: 25437913
DOI: 10.1038/nsmb.2924

Experimental method

X-RAY DIFFRACTION (2.83 Å)