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Nat Chem Biol. 2017 Jan;13(1):62-68. doi: 10.1038/nchembio.2231. Epub 2016 Nov 7.

Inhibition of RAS function through targeting an allosteric regulatory site.

Author information

1
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA.
2
University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA.
3
Jesse Brown VA Medical Center, Chicago, Illinois, USA.
4
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
5
Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA.
6
Department of Medicine, New York University Langone Medical Center, New York, New York, USA.
7
Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, Texas, USA.
8
Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, Canada.
9
Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
10
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
12
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
13
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York, USA.

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.

PMID:
27820802
PMCID:
PMC5193369
DOI:
10.1038/nchembio.2231
[Indexed for MEDLINE]
Free PMC Article

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