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Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

1
Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan
2
Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Silvano Geremia
Molecules 2019, 24(18), 3308; https://doi.org/10.3390/molecules24183308
Received: 29 July 2019 / Revised: 9 September 2019 / Accepted: 10 September 2019 / Published: 11 September 2019
(This article belongs to the Special Issue Frontier of Protein Crystallography)
Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery. View Full-Text
Keywords: small GTPases; GEF; crystal structure; regulation mechanism; local protein unfolding small GTPases; GEF; crystal structure; regulation mechanism; local protein unfolding
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Toma-Fukai, S.; Shimizu, T. Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules 2019, 24, 3308.

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