Transmembrane receptors for hormones, neurotransmitters, light, and odorants mediate their cellular effects by activating heterotrimeric guanine nucleotide-binding proteins (G proteins), Crystal structures have revealed contact surfaces between G protein subunits, but not the surfaces or molecular mechanism through which G alpha beta gamma responds to activation by transmembrane receptors, Such a surface was identified from the results of testing 100 mutant alpha subunits of the retinal G protein transducin for their ability to interact with rhodopsin, Sites at which alanine substitutions impaired this interaction mapped to two distinct G alpha surfaces : a beta gamma-binding surface and a putative receptor-interacting surface. On the basis of these results a mechanism for receptor-catalyzed exchange of guanosine diphosphate for guanosine triphosphate is proposed.