Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases
| Autor: | Alan Merk, Jana Ognjenovic, Kathryn Wong, Jeroen P. Roose, Yasushi Kondo, Sriram Subramaniam, Kayla Kulhanek, Deepti Karandur, Saikat Banerjee, John Kuriyan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Models Molecular Proto-Oncogene Proteins B-raf General Science & Technology Protein domain Spodoptera Molecular Dynamics Simulation medicine.disease_cause Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Protein Domains Models Catalytic Domain medicine Animals Humans Phosphorylation Mutation Multidisciplinary biology Chemistry Kinase Cryoelectron Microscopy Molecular Active site biology.organism_classification Cell biology 030104 developmental biology Protein kinase domain 14-3-3 Proteins Cell culture 030220 oncology & carcinogenesis biology.protein Insect Proteins Protein Multimerization |
| Zdroj: | Science (New York, N.Y.), vol 366, iss 6461 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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