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Small GTPases. 2017 Jul 10:1-10. doi: 10.1080/21541248.2017.1333188. [Epub ahead of print]

Targeting the α4-α5 interface of RAS results in multiple levels of inhibition.

Spencer-Smith R1,2,3, Li L1,2,3, Prasad S1, Koide A4,5,6, Koide S4,5,7, O'Bryan JP1,2,3.

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a Department of Pharmacology , University of Illinois at Chicago , Chicago , IL , USA.
b University of Illinois Cancer Center, University of Illinois at Chicago , Chicago , IL , USA.
c Jesse Brown VA Medical Center , Chicago , IL , USA.
d Department of Biochemistry and Molecular Biology , University of Chicago , Chicago , IL , USA.
e Perlmutter Cancer Center, New York University Langone Medical Center , New York , NY , USA.
f Department of Medicine , New York University School of Medicine , New York , NY , USA.
g Department of Biochemistry and Molecular Pharmacology , New York University School , New York , NY , USA.


Generation of RAS-targeted therapeutics has long been considered a "holy grail" in cancer research. However, a lack of binding pockets on the surface of RAS and its picomolar affinity for guanine nucleotides have made isolation of inhibitors particularly challenging. We recently described a monobody, termed NS1, that blocks RAS signaling and oncogenic transformation. NS1 binds to the α4-β6-α5 interface of H-RAS and K-RAS thus preventing RAS dimerization and nanoclustering, which in turn prevents RAS-stimulated dimerization and activation of RAF. Interestingly, NS1 reduces interaction of oncogenic K-RAS, but not H-RAS, with RAF and reduces K-RAS plasma membrane localization. Here, we show that these isoform specific effects of NS1 on RAS:RAF are due to the distinct hypervariable regions of RAS isoforms. NS1 inhibited wild type RAS function by reducing RAS GTP levels. These findings reveal that NS1 disrupts RAS signaling through a mechanism that is more complex than simply inhibiting RAS dimerization and nanoclustering.


H-RAS; K-RAS; NS1 monobody; RAS chimera; RAS dimerization; RAS inhibitor; RAS nanoclustering

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