期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 1, 页码 62-68出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2231
关键词
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资金
- DOE Office of Science [DE-AC02-06CH11357]
- US National Institutes of Health (NIH) F31 Predoctoral Award [CA192822]
- CIHR award [FDN 143277]
- Merit Review Award from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service [1I01BX002095]
- NIH [CA116708, CA201717, GM090324]
- Catalyst award from the Chicago Biomedical Consortium
- Searles Funds at the Chicago Community Trust
RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the alpha 4-beta 6-alpha 5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the alpha 4-beta 6-alpha 5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.
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