| Literature DB >> 27820802 |
Russell Spencer-Smith1,2,3, Akiko Koide4,5,6, Yong Zhou7, Raphael R Eguchi4, Fern Sha4, Priyanka Gajwani1,2, Dianicha Santana1,2, Ankit Gupta4,5, Miranda Jacobs1,2, Erika Herrero-Garcia1,2,3, Jacqueline Cobbert1,2, Hugo Lavoie8, Matthew Smith9, Thanashan Rajakulendran10,11,12, Evan Dowdell4, Mustafa Nazir Okur1,2, Irina Dementieva4, Frank Sicheri10,11,12, Marc Therrien8, John F Hancock7, Mitsuhiko Ikura9, Shohei Koide4,5,13, John P O'Bryan1,2,3.
Abstract
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 α4-β6-α5 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 α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.Entities:
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Year: 2016 PMID： 27820802 PMCID： PMC5193369 DOI： 10.1038/nchembio.2231
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040