5UFE

Wild-type K-Ras(GNP)/R11.1.6 complex

Summary for 5UFE

• Entry DOI: 10.2210/pdb5ufe/pdb
• Related: 5UFQ
• Descriptor: GTPase KRas, R11.1.6, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (9 entities in total)
• Functional Keywords: ras, gtpase, inhibitor, binder, hydrolase-de novo protein complex, hydrolase/de novo protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 27542.16

Authors

Parker, J.A.,Mattos, C. (deposition date: 2017-01-04, release date: 2017-08-02, Last modification date: 2023-10-04)

Primary citation

Kauke, M.J.,Traxlmayr, M.W.,Parker, J.A.,Kiefer, J.D.,Knihtila, R.,McGee, J.,Verdine, G.,Mattos, C.,Wittrup, K.D.
An engineered protein antagonist of K-Ras/B-Raf interaction.
Sci Rep, 7:5831-5831, 2017

PubMed 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.

PubMed: 28724936
DOI: 10.1038/s41598-017-05889-7

Experimental method

X-RAY DIFFRACTION (2.302 Å)