Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases

American Association for the Advancement of Science (AAAS) - Tập 366 Số 6461 - Trang 109-115 - 2019
Yasushi Kondo1,2, Jana Ognjenović3, Saikat Banerjee4, Deepti Karandur1,2,5, Alan Merk3, Kayla Kulhanek4, Kathryn Wong1,2, Jeroen P. Roose4, Sriram Subramaniam6, John Kuriyan1,7,2,8,5
1California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA
2Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
3Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20814, USA.
4Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143 USA
5Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720 USA
6University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada
7Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA
8Divisions of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Tóm tắt

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

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American Association for the Advancement of Science (AAAS)

Tập 366 Số 6461

109-115

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