An engineered protein antagonist of K-Ras/B-Raf interaction

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...

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Autores principales:	Monique J. Kauke, Michael W. Traxlmayr, Jillian A. Parker, Jonathan D. Kiefer, Ryan Knihtila, John McGee, Greg Verdine, Carla Mattos, K. Dane Wittrup
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2ce4911947be421fa5711cae0ecd11de
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spelling	oai:doaj.org-article:2ce4911947be421fa5711cae0ecd11de2021-12-02T16:07:02ZAn engineered protein antagonist of K-Ras/B-Raf interaction10.1038/s41598-017-05889-72045-2322https://doaj.org/article/2ce4911947be421fa5711cae0ecd11de2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05889-7https://doaj.org/toc/2045-2322Abstract 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.Monique J. KaukeMichael W. TraxlmayrJillian A. ParkerJonathan D. KieferRyan KnihtilaJohn McGeeGreg VerdineCarla MattosK. Dane WittrupNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Monique J. Kauke Michael W. Traxlmayr Jillian A. Parker Jonathan D. Kiefer Ryan Knihtila John McGee Greg Verdine Carla Mattos K. Dane Wittrup An engineered protein antagonist of K-Ras/B-Raf interaction
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.
format	article
author	Monique J. Kauke Michael W. Traxlmayr Jillian A. Parker Jonathan D. Kiefer Ryan Knihtila John McGee Greg Verdine Carla Mattos K. Dane Wittrup
author_facet	Monique J. Kauke Michael W. Traxlmayr Jillian A. Parker Jonathan D. Kiefer Ryan Knihtila John McGee Greg Verdine Carla Mattos K. Dane Wittrup
author_sort	Monique J. Kauke
title	An engineered protein antagonist of K-Ras/B-Raf interaction
title_short	An engineered protein antagonist of K-Ras/B-Raf interaction
title_full	An engineered protein antagonist of K-Ras/B-Raf interaction
title_fullStr	An engineered protein antagonist of K-Ras/B-Raf interaction
title_full_unstemmed	An engineered protein antagonist of K-Ras/B-Raf interaction
title_sort	engineered protein antagonist of k-ras/b-raf interaction
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2ce4911947be421fa5711cae0ecd11de
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An engineered protein antagonist of K-Ras/B-Raf interaction

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