dc.contributor.author | Parker, Jillian A. | |
dc.contributor.author | Kiefer, Jonathan D. | |
dc.contributor.author | Knihtila, Ryan | |
dc.contributor.author | McGee, John | |
dc.contributor.author | Verdine, Greg | |
dc.contributor.author | Mattos, Carla | |
dc.contributor.author | Kauke, Monique Jacqueline | |
dc.contributor.author | Traxlmayr, Michael | |
dc.contributor.author | Wittrup, Karl Dane | |
dc.date.accessioned | 2017-12-11T19:28:20Z | |
dc.date.available | 2017-12-11T19:28:20Z | |
dc.date.issued | 2017-07 | |
dc.date.submitted | 2017-03 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/112691 | |
dc.description.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. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant 5-R01-CA096504-15) | en_US |
dc.publisher | Nature Publishing Group | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1038/s41598-017-05889-7 | en_US |
dc.rights | Creative Commons Attribution 4.0 International | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_US |
dc.source | Nature | en_US |
dc.title | An engineered protein antagonist of K-Ras/B-Raf interaction | en_US |
dc.type | Article | en_US |
dc.identifier.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) | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemical Engineering | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.contributor.mitauthor | Kauke, Monique Jacqueline | |
dc.contributor.mitauthor | Traxlmayr, Michael | |
dc.contributor.mitauthor | Wittrup, Karl Dane | |
dc.relation.journal | Scientific Reports | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2017-12-11T17:01:32Z | |
dspace.orderedauthors | Kauke, Monique J.; Traxlmayr, Michael W.; Parker, Jillian A.; Kiefer, Jonathan D.; Knihtila, Ryan; McGee, John; Verdine, Greg; Mattos, Carla; Wittrup, K. Dane | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-0013-3941 | |
dc.identifier.orcid | https://orcid.org/0000-0002-2108-582X | |
dc.identifier.orcid | https://orcid.org/0000-0003-2398-5896 | |
mit.license | PUBLISHER_CC | en_US |