6UAN

B-Raf:14-3-3 complex

Summary for 6UAN

• Entry DOI: 10.2210/pdb6uan/pdb
• EMDB information: 20708
• Descriptor: 14-3-3 zeta, Serine/threonine-protein kinase B-raf (2 entities in total)
• Functional Keywords: complex kinase, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 225780.87

Authors

Kondo, Y.,Ognjenovic, J.,Banerjee, S.,Karandur, D.,Merk, A.,Kulhanek, K.,Wong, K.,Roose, J.P.,Subramaniam, S.,Kuriyan, J. (deposition date: 2019-09-11, release date: 2019-09-25, Last modification date: 2024-11-13)

Primary citation

Kondo, Y.,Ognjenovic, J.,Banerjee, S.,Karandur, D.,Merk, A.,Kulhanek, K.,Wong, K.,Roose, J.P.,Subramaniam, S.,Kuriyan, J.
Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases.
Science, 366:109-115, 2019

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 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.

PubMed: 31604311
DOI: 10.1126/science.aay0543

Experimental method

ELECTRON MICROSCOPY (3.9 Å)