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Inhibition of RAS function through targeting an allosteric regulatory site

Nature Chemical Biology volume 13, pages 62–68 (2017)Cite this article

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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.

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Figure 1: RAS-specific monobody targets H-RAS and K-RAS.
Figure 2: NS1 inhibits RAS-mediated signaling and transformation.
Figure 3: NS1 targets the α4–α5 interface in RAS distal to switch regions.
Figure 4: NS1 targets a putative RAS dimerization interface.
Figure 5: NS1 blocks RAS dimerization and nanoclustering and subsequent RAF activation.
Figure 6: Effect of NS1 on oncogenic RAS activation of RAF.

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Acknowledgements

This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract number DE-AC02-06CH11357. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. We thank J. Kuriyan and Y. Kondo (University of California, Berkeley (UC Berkeley)) for the purified Sos protein; S. Campbell (University of North Carolina at Chapel Hill (UNC)) for the K-RAS expression construct; A. Cox (UNC) for the N-RAS(G12D) construct; W. Hahn (Dana-Farber Cancer Institute) for the pBabe-Puro-MEK-DD (Addgene plasmid 15268); G. Clark (University of Louisville) for pCGN-RAF; B. Kreutz (University of Illinois at Chicago) for assistance with the fluorescent nucleotide exchange assays; D. Morrison (National Cancer Institute, NIH) for purified MEK(K97R); A. Aplin (Thomas Jefferson University) for A375 human melanoma cells; and C.-D. Hu (Purdue University) for expression constructs consisting of the Flag-tagged N terminus or HA-tagged C terminus of Venus. R.S.-S. is supported by a US National Institutes of Health (NIH) F31 Predoctoral Award (CA192822). This work was supported in part by a CIHR award to F. Sicheri (FDN 143277), a Merit Review Award (1I01BX002095) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service to J.P.O., NIH awards to J.P.O. (CA116708 and CA201717) and S.K. (GM090324) and a Catalyst award from the Chicago Biomedical Consortium with support from the Searles Funds at the Chicago Community Trust to S.K. and J.P.O.

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Authors and Affiliations

  1. Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA

    Russell Spencer-Smith, Priyanka Gajwani, Dianicha Santana, Miranda Jacobs, Erika Herrero-Garcia, Jacqueline Cobbert, Mustafa Nazir Okur & John P O'Bryan

  2. University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA

    Russell Spencer-Smith, Priyanka Gajwani, Dianicha Santana, Miranda Jacobs, Erika Herrero-Garcia, Jacqueline Cobbert, Mustafa Nazir Okur & John P O'Bryan

  3. Jesse Brown VA Medical Center, Chicago, Illinois, USA

    Russell Spencer-Smith, Erika Herrero-Garcia & John P O'Bryan

  4. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA

    Akiko Koide, Raphael R Eguchi, Fern Sha, Ankit Gupta, Evan Dowdell, Irina Dementieva & Shohei Koide

  5. Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA

    Akiko Koide, Ankit Gupta & Shohei Koide

  6. Department of Medicine, New York University Langone Medical Center, New York, New York, USA

    Akiko Koide

  7. Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, Texas, USA

    Yong Zhou & John F Hancock

  8. Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada

    Hugo Lavoie & Marc Therrien

  9. Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada

    Matthew Smith & Mitsuhiko Ikura

  10. Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada

    Thanashan Rajakulendran & Frank Sicheri

  11. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Thanashan Rajakulendran & Frank Sicheri

  12. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

    Thanashan Rajakulendran & Frank Sicheri

  13. Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York, USA

    Shohei Koide

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  1. Russell Spencer-Smith
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Contributions

R.S.-S., A.K., F. Sicheri, M.I., J.F.H., M.T., S.K. and J.P.O'B. designed the study; M.N.O. and I.D. prepared protein for monobody isolation; A.K. and E.D. performed library selection and identified NS1; I.D., M.S. and M.I. performed and interpreted NMR experiments; T.R. and F. Sicheri analyzed RAS structures in the PDB; R.S.-S., A.K., E.H.-G., D.S., P.G., J.C., M.J. and M.N.O. performed biochemical and cell biology experiments; R.R.E., F. Sha, A.G. and S.K. determined X-ray structure of monobody–RAS complex; Y.Z. and J.F.H. performed the nanoclustering analysis; H.L. and M.T. performed the BRET analysis; R.S.-S., F. Sicheri., S.K. and J.P.O. wrote the manuscript, and all authors commented and approved the manuscript.

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Correspondence to Shohei Koide or John P O'Bryan.

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Competing interests

S.K. and A.K. are inventors on a patent application filed by the University of Chicago that covers a design of monobody libraries (US 13/813,409). S.K., A.K. and J.P.O'B. are inventors on a patent application jointly filed by the University of Chicago and University of Illinois that covers the NS1 monobody.

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Supplementary Results, Supplementary Tables 1–3 and Supplementary Figures 1–21. (PDF 15103 kb)

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Spencer-Smith, R., Koide, A., Zhou, Y. et al. Inhibition of RAS function through targeting an allosteric regulatory site. Nat Chem Biol 13, 62–68 (2017). https://doi.org/10.1038/nchembio.2231

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