A large super-family of trans-membrane receptors control cellular responses to diverse extracellular signals by catalyzing activation of specific types of hetero-trimeric GTP-binding proteins. How these receptors promote nucleotide exchange on G-protein a-subunits to initiate signal amplification is unknown. The three-dimensional structure of the Gt a-subunit C-terminal undecapeptide, Gta IKENLKDCGLF, was determined by TRNOE spectroscopy while bound to photo-excited rhodopsin. The structure of the synthetic undecapeptide was confirmed by mass spectrometry. Light-activation of rhodopsin causes a dramatic shift from a disordered conformation of Gta to a binding motif with a helical turn followed by an open reverse turn centered at Gly348, a helix-terminating C-capping motif of an aL-type. Docking of the NMR structure to the GDP-bound X-ray structure of Gt reveals that photo-excited rhodopsin promotes the formation of a continuous helix over residues 325-346 t erminated by the C-terminal helical cap with a unique cluster of crucial hydrophobic side chains. A molecular mechanism by which activated receptors control G-proteins through reversible conformational changes at the receptor-G protein interface is demonstrated.
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