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J Biol Chem, Vol. 274, Issue 24, 16669-16672, June 11, 1999

COMMUNICATION
Structure of G_i1·GppNHp, Autoinhibition in a G Protein-Substrate Complex

David E. Coleman and Stephen R. Sprang^§

From the ^§ Howard Hughes Medical Institute and the  Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050

The structure of the G protein G_i1 complexed with the nonhydrolyzable GTP analog guanosine-5'-(-imino)triphosphate (GppNHp) has been determined at a resolution of 1.5 Å. In the active site of G_i1·GppNHp, a water molecule is hydrogen bonded to the side chain of Glu⁴³ and to an oxygen atom of the -phosphate group. The side chain of the essential catalytic residue Gln²⁰⁴ assumes a conformation which is distinctly different from that observed in complexes with either guanosine 5'-O-3-thiotriphosphate or the transition state analog GDP·AlF₄. Hydrogen bonding and steric interactions position Gln²⁰⁴ such that it interacts with a presumptive nucleophilic water molecule, but cannot interact with the pentacoordinate transition state. Gln²⁰⁴ must be released from this auto-inhibited state to participate in catalysis. RGS proteins may accelerate the rate of GTP hydrolysis by G protein  subunits, in part, by inserting an amino acid side chain into the site occupied by Gln²⁰⁴, thereby destabilizing the auto-inhibited state of G.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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