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| Title | Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases. |
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| Journal, issue, pages | Science, Vol. 366, Issue 6461, Page 109-115, Year 2019 |
| Publish date | Oct 4, 2019 |
 Authors | Yasushi Kondo / Jana Ognjenović / Saikat Banerjee / Deepti Karandur / Alan Merk / Kayla Kulhanek / Kathryn Wong / Jeroen P Roose / Sriram Subramaniam / John Kuriyan /   |
| PubMed 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 ...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 ~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. |
 External links | Science / PubMed:31604311 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.9 Å |
| Structure data | EMDB-20708, PDB-6uan: |
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 Keywords |  SIGNALING PROTEIN / Complex Kinase |
Asian cotton leafworm (butterflies/moths)