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Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit.


Van Eps NNed , Preininger AM Anita M , Alexander N Nathan , Kaya AI Ali I , Meier S Scott , Meiler J Jens , Hamm HE Heidi E , Hubbell WL Wayne L . Proceedings of the National Academy of Sciences of the United States of America. 2011 6 7; 108(23). 9420-4


In G-protein signaling, an activated receptor catalyzes GDP/GTP exchange on the G(α) subunit of a heterotrimeric G protein. In an initial step, receptor interaction with G(α) acts to allosterically trigger GDP release from a binding site located between the nucleotide binding domain and a helical domain, but the molecular mechanism is unknown. In this study, site-directed spin labeling and double electron-electron resonance spectroscopy are employed to reveal a large-scale separation of the domains that provides a direct pathway for nucleotide escape. Cross-linking studies show that the domain separation is required for receptor enhancement of nucleotide exchange rates. The interdomain opening is coupled to receptor binding via the C-terminal helix of G(α), the extension of which is a high-affinity receptor binding element.