Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases
Copyright policy )Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases
The yin and yang of Raf inhibition Many human melanomas contain an overactive form of Raf kinase (B-Raf). Inhibitors are effective against the mutant B-Raf, but, paradoxically, they activate wild-type B-Raf, limiting their therapeutic potential. Kondo et al. determined the structure of a phosphorylated B-Raf dimer in complex with the scaffold protein 14-3-3 by cryo–electron microscopy. Although both kinases are in the active conformation, one is blocked by the C-terminal tail of the other. This configuration inhibits one active site but also stabilizes the dimer in the active conformation. Understanding this mechanism provides a framework for development of inhibitors that do not activate wild-type Raf. Science , this issue p. 109
- University of California, Berkeley United States
- University of California, San Francisco United States
- University of British Columbia Canada
- Lawrence Berkeley National Laboratory United States
- QB3 United States
Models, Molecular, Proto-Oncogene Proteins B-raf, General Science & Technology, Cryoelectron Microscopy, Molecular, Biological Sciences, Molecular Dynamics Simulation, Spodoptera, Cell Line, Mice, 14-3-3 Proteins, Protein Domains, Models, Catalytic Domain, Mutation, Animals, Humans, Insect Proteins, Biochemistry and Cell Biology, Phosphorylation, Protein Multimerization, Cancer
Models, Molecular, Proto-Oncogene Proteins B-raf, General Science & Technology, Cryoelectron Microscopy, Molecular, Biological Sciences, Molecular Dynamics Simulation, Spodoptera, Cell Line, Mice, 14-3-3 Proteins, Protein Domains, Models, Catalytic Domain, Mutation, Animals, Humans, Insect Proteins, Biochemistry and Cell Biology, Phosphorylation, Protein Multimerization, Cancer
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