An engineered protein antagonist of K-Ras/B-Raf interaction
Author(s)Parker, Jillian A.; Kiefer, Jonathan D.; Knihtila, Ryan; McGee, John; Verdine, Greg; Mattos, Carla; Kauke, Monique Jacqueline; Traxlmayr, Michael; Wittrup, Karl Dane; ... Show more Show less
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Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemical Engineering
Nature Publishing Group
Kauke, Monique J. et al. “An Engineered Protein Antagonist of K-Ras/B-Raf Interaction.” Scientific Reports 7, 1 (July 2017): 5831 © 2017 The Author(s)
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