Mechanism of GTP hydrolysis by G-protein alpha subunits.
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 p21ras cause tumors in man. A conserved glutamic residue in the alpha 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 Gi alpha 1 refute this hypothesis. Based on the structure of the complex of Gi alpha 1 with GDP, Mg2+, and AlF-4, which appears to resemble the transition state for GTP hydrolysis, we believe that Gln-204 of Gi alpha 1, rather than Glu-207, supports catalysis of GTP hydrolysis by stabilization of the transition state.
Kleuss
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Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235.
Raw
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Lee
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Sprang
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Gilman
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AG
D017607:Aluminum Compounds / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry; D004926:Escherichia coli; D005459:Fluorides / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D046911:Macromolecular Substances; D008274:Magnesium / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D010761:Phosphorus Radioisotopes; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D017607:Aluminum Compounds; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D010761:Phosphorus Radioisotopes; D011994:Recombinant Proteins; C050992:tetrafluoroaluminate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D004247:DNA; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D008274:Magnesium; D005459:Fluorides