Skip to main content

Hamm Lab

Mechanism of the receptor-catalyzed activation of heterotrimeric G proteins.

AUTHORS

Oldham WMWilliam M , Van Eps N Ned , Preininger AM Anita M , Hubbell WL Wayne L , Hamm HE Heidi E . Nature structural & molecular biology. 2006 9 ; 13(9). 772-7

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.