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dc.contributor.author
Kauke, Monique J.
dc.contributor.author
Traxlmayr, Michael W.
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
Wittrup, K. Dane
dc.date.accessioned
2017-11-17T13:35:30Z
dc.date.available
2017-10-06T03:18:19Z
dc.date.available
2017-11-17T13:35:30Z
dc.date.issued
2017
dc.identifier.issn
2045-2322
dc.identifier.other
10.1038/s41598-017-05889-7
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/191507
dc.identifier.doi
10.3929/ethz-b-000191507
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.format
application/pdf
dc.language.iso
en
en_US
dc.publisher
Nature Publishing Group
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
An engineered protein antagonist of K-Ras/B-Raf interaction
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2017-07-19
ethz.journal.title
Scientific Reports
ethz.journal.volume
7
en_US
ethz.journal.abbreviated
Sci Rep
ethz.pages.start
5831
en_US
ethz.size
9 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2017-10-06T03:18:26Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-11-17T13:35:34Z
ethz.rosetta.lastUpdated
2021-02-14T20:24:37Z
ethz.rosetta.versionExported
true
ethz.COinS
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