Conformational ensembles of SOS1 upon association with K-Ras4B

Authors

• T Liao
• H Jang
• D Fushman
• R Nussinov

Abstract

The son of sevenless (SOS) is a guanine nucleotide exchange factor (GEF) that exchanges GDP by GTP and activates Ras. Active Ras leads to downstream signaling, inducing cell proliferation. SOS has two Ras binding sites: Ras exchanger motif (Rem) domain (Ras allosteric site) and catalytic Cdc25 domain (Ras active site). Apo SOS is in an inactive state in which the Rem domain sterically obstructs the Ras binding site in the Cdc25 domain. When the GTP-bound Ras binds to the Rem domain, it relieves the steric occlusion and thereby activates SOS. The Cdc25 domain is now able to associate with the GDP-bound Ras and activates it. Ras binding to the allosteric site induces conformational changes of SOS, leading to Ras activation. Although crystal structure of Ras-SOS complex provided information of molecular interactions, the exact mechanism of the conformational changes of SOS and Ras activation remain unclear. Our goal is to simulate the SOS-Ras complex and sample the SOS conformational ensembles. A better understanding of SOS structure will aid the drug discovery strategies.

Scientific Focus Area: Structural Biology

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