Journal
SCIENCE
Volume 366, Issue 6461, Pages 109-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aay0543
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Funding
- NIH [P01-AI091580]
- UCSF IRACDA grant [K12GM081266]
- Aqueduct Foundation
- VGH & UBC Hospital Foundation
- Canada Excellence Research Chair Award
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Raf kinases are important cancer drug targets. Paradoxically, many B-Raf inhibitors induce the activation of Raf kinases. Cryo-electron microscopy structural analysis of a phosphorylated B-Raf kinase domain dimer in complex with dimeric 14-3-3, at a resolution of similar to 3.9 angstroms, shows an asymmetric arrangement in which one kinase is in a canonical active conformation. The distal segment of the C-terminal tail of this kinase interacts with, and blocks, the active site of the cognate kinase in this asymmetric arrangement. Deletion of the C-terminal segment reduces Raf activity. The unexpected asymmetric quaternary architecture illustrates how the paradoxical activation of Raf by kinase inhibitors reflects an innate mechanism, with 14-3-3 facilitating inhibition of one kinase while maintaining activity of the other. Conformational modulation of these contacts may provide new opportunities for Raf inhibitor development.
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