An engineered protein antagonist of K-Ras/B-Raf interaction
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Kauke_et_al-2017-Scientific_Reports.pdf
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Author(s)
Parker, Jillian A.
Kiefer, Jonathan D.
Knihtila, Ryan
McGee, John
Verdine, Greg
Mattos, Carla
Kauke, Monique Jacqueline
Traxlmayr, Michael
Wittrup, Karl Dane
Date Issued
July 2017
Journal
Scientific Reports
Publisher
Nature Publishing Group
Citation
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)
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution 4.0 International
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DOI of Published Version
https://doi.org/10.1038/s41598-017-05889-7
