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Sci Rep. 2017 Jul 19;7(1):5831. doi: 10.1038/s41598-017-05889-7.

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

Author information

1
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
3
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA.
4
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland.
5
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
6
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
7
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA.
8
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. wittrup@mit.edu.
9
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. wittrup@mit.edu.
10
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. wittrup@mit.edu.

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.

PMID:
28724936
PMCID:
PMC5517481
DOI:
10.1038/s41598-017-05889-7
[Indexed for MEDLINE]
Free PMC Article

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