Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases-Reference-Cited by-同舟云学术

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

Published:2019-10-04 Issue:6461 Volume:366 Page:109-115
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Kondo Yasushi¹²^ORCID,Ognjenović Jana³^ORCID,Banerjee Saikat⁴,Karandur Deepti¹²⁵^ORCID,Merk Alan³,Kulhanek Kayla⁴^ORCID,Wong Kathryn¹²,Roose Jeroen P.⁴^ORCID,Subramaniam Sriram⁶^ORCID,Kuriyan John¹²⁵⁷⁸^ORCID

Affiliation:

1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

2. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.

3. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20814, USA.

4. Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.

5. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.

6. University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

7. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.

8. Divisions of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Abstract

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

Funder

NIH Office of the Director

Canada Excellence Research Chairs, Government of Canada

UCSF IRACDA

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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