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      Inhibition of RAS function through targeting an allosteric regulatory site


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          RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here, we describe a functionally critical region of RAS located outside the effector lobe that can be targeted for inhibition. We developed a synthetic binding protein (monobody), termed NS1, that bound with high affinity to both GTP- and GDP-bound states of H- and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H- 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 disrupting RAS dimerization/nanoclustering, which in turn blocked 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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          Most cited references43

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          Ras oncogenes: split personalities.

          Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.
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            Shape complementarity at protein/protein interfaces.

            A new statistic Sc, which has a number of advantages over other measures of packing, is used to examine the shape complementarity of protein/protein interfaces selected from the Brookhaven Protein Data Bank. It is shown using Sc that antibody/antigen interfaces as a whole exhibit poorer shape complementarity than is observed in other systems involving protein/protein interactions. This result can be understood in terms of the fundamentally different evolutionary history of particular antibody/antigen associations compared to other systems considered, and in terms of the differing chemical natures of the interfaces.
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              The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

              The three-dimensional structure of the complex between human H-Ras bound to guanosine diphosphate and the guanosine triphosphatase (GTPase)-activating domain of the human GTPase-activating protein p120GAP (GAP-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. The structure shows the partly hydrophilic and partly hydrophobic nature of the communication between the two molecules, which explains the sensitivity of the interaction toward both salts and lipids. An arginine side chain (arginine-789) of GAP-334 is supplied into the active site of Ras to neutralize developing charges in the transition state. The switch II region of Ras is stabilized by GAP-334, thus allowing glutamine-61 of Ras, mutation of which activates the oncogenic potential, to participate in catalysis. The structural arrangement in the active site is consistent with a mostly associative mechanism of phosphoryl transfer and provides an explanation for the activation of Ras by glycine-12 and glutamine-61 mutations. Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state.

                Author and article information

                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                10 December 2016
                07 November 2016
                January 2017
                01 July 2017
                : 13
                : 1
                : 62-68
                [1 ]Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60623, USA
                [2 ]University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60623, USA
                [3 ]Jesse Brown VA Medical Center, Chicago, IL 60612, USA
                [4 ]Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
                [5 ]Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA
                [6 ]Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA
                [7 ]Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA
                [8 ]Institute for Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, H3C 3J7 Canada
                [9 ]Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, M5G 2M9 Canada
                [10 ]Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario M5G 1X5, Canada
                [11 ]Departments of Molecular Genetics and Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
                [12 ]Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA
                Author notes
                Correspondence and requests for materials should be addressed to S.K. ( Shohei.Koide@ 123456nyumc.org ) and J.P.O. ( obryanj@ 123456uic.edu )
                PMC5193369 PMC5193369 5193369 nihpa833024

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