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Mechanism of GTP hydrolysis by G-protein α subunits

Proceedings of the National Academy of Sciences of the United States of America, Vol: 91, Issue: 21, Page: 9828-9831
1994
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Hydrolysis of GTP by a variety of guanine nucleotide-binding proteins is a crucial step for regulation of these biological switches. Mutations that impair the GTPase activity of certain heterotrimeric signal-transducing G proteins or of p21(ras) cause tumors in man. A conserved glutamic residue in the α subunit of G proteins has been hypothesized to serve as a general base, thereby activating a water molecule for nucleophilic attack on GTP. The results of mutagenesis of this residue (Glu-207) in G(iα1) refute this hypothesis. Based on the structure of the complex of G(iα1) with GDP, Mg2+, and AlF4/-, which appears to resemble the transition state for GTP hydrolysis, we believe that Glu-204 of G(iα1), rather than Glu-207, supports catalysis of GTP hydrolysis by stabilization of the transition state.

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