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

  1. Author:
    Kondo, Yasushi
    Ognjenovic,Jana
    Banerjee, Saikat
    Karandur, Deepti
    Merk,Alan
    Kulhanek, Kayla
    Wong, Kathryn
    Roose, Jeroen P.
    Subramaniam, Sriram
    Kuriyan, John

  2. Author Address

    Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA.NCI, Lab Cell Biol, Ctr Canc Res, Bethesda, MD 20814 USA.Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA.Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA.Univ British Columbia, Vancouver, BC V6T 1Z3, Canada.Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.Lawrence Berkeley Natl Lab, Div Mol Biophys, Berkeley, CA 94720 USA.Lawrence Berkeley Natl Lab, Div Integrated Bioimaging, Berkeley, CA 94720 USA.Frederick Natl Lab Canc Res, Frederick, MD 21701 USA.USC, Keck Sch Med, Los Angeles, CA 90033 USA.
    1. Year: 2019
    2. Date: OCT 4
  2. Journal: SCIENCE
  3. AMER ASSOC ADVANCEMENT SCIENCE,
    1. 366
    2. 6461
    3. Pages: 109-+
  5. Type of Article: Article
  6. ISSN: 0036-8075
  1. Abstract:

    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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External Sources

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  2. DOI: 10.1126/science.aay0543
  3. View record in Web of Science®
  4. WOS: 000489147000066

Library Notes

  1. Fiscal Year: FY2019-2020
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