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- W2548573003 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." @default.
- W2548573003 created "2016-11-11" @default.
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- W2548573003 date "2016-11-07" @default.
- W2548573003 modified "2023-10-02" @default.
- W2548573003 title "Inhibition of RAS function through targeting an allosteric regulatory site" @default.
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- W2548573003 doi "https://doi.org/10.1038/nchembio.2231" @default.
- W2548573003 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5193369" @default.
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- W2548573003 hasPublicationYear "2016" @default.
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