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  • Title: Mechanism of the receptor-catalyzed activation of heterotrimeric G proteins.
    Author: Oldham WM, Van Eps N, Preininger AM, Hubbell WL, Hamm HE.
    Journal: Nat Struct Mol Biol; 2006 Sep; 13(9):772-7. PubMed ID: 16892066.
    Abstract:
    Heptahelical receptors activate intracellular signaling pathways by catalyzing GTP for GDP exchange on the heterotrimeric G protein alpha subunit (G alpha). Despite the crucial role of this process in cell signaling, little is known about the mechanism of G protein activation. Here we explore the structural basis for receptor-mediated GDP release using electron paramagnetic resonance spectroscopy. Binding to the activated receptor (R*) causes an apparent rigid-body movement of the alpha5 helix of G alpha that would perturb GDP binding at the beta6-alpha5 loop. This movement was not observed when a flexible loop was inserted between the alpha5 helix and the R*-binding C terminus, which uncouples R* binding from nucleotide exchange, suggesting that this movement is necessary for GDP release. These data provide the first direct observation of R*-mediated conformational changes in G proteins and define the structural basis for GDP release from G alpha.
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