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DOI | 10.1126/science.aay0543 |
Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases | |
Kondo, Yasushi1,2; Ognjenovic, Jana3,10; Banerjee, Saikat4; Karandur, Deepti1,2,5; Merk, Alan3,10; Kulhanek, Kayla4; Wong, Kathryn1,2,11; Roose, Jeroen P.4; Subramaniam, Sriram6; Kuriyan, John1,2,5,7,8,9 | |
2019-10-04 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 366期号:6461页码:109-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Canada |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000489147000066 |
WOS关键词 | MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; PROTEIN-KINASES ; BRAF ; ACTIVATION ; DOMAIN ; MECHANISM ; MUTANT ; PHOSPHORYLATION ; VISUALIZATION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202453 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA; 2.Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA; 3.NCI, Lab Cell Biol, Ctr Canc Res, Bethesda, MD 20814 USA; 4.Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA; 5.Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA; 6.Univ British Columbia, Vancouver, BC V6T 1Z3, Canada; 7.Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA; 8.Lawrence Berkeley Natl Lab, Div Mol Biophys, Berkeley, CA 94720 USA; 9.Lawrence Berkeley Natl Lab, Div Integrated Bioimaging, Berkeley, CA 94720 USA; 10.Frederick Natl Lab Canc Res, Frederick, MD 21701 USA; 11.USC, Keck Sch Med, Los Angeles, CA 90033 USA |
推荐引用方式 GB/T 7714 | Kondo, Yasushi,Ognjenovic, Jana,Banerjee, Saikat,et al. Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases[J]. SCIENCE,2019,366(6461):109-+. |
APA | Kondo, Yasushi.,Ognjenovic, Jana.,Banerjee, Saikat.,Karandur, Deepti.,Merk, Alan.,...&Kuriyan, John.(2019).Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases.SCIENCE,366(6461),109-+. |
MLA | Kondo, Yasushi,et al."Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases".SCIENCE 366.6461(2019):109-+. |
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