Evolutionarily conserved G(alpha beta gamma) binding surfaces support a model of the G protein-receptor complex

The pivotal role of G proteins in sensory, hormonal, inflammatory, and proliferative responses has provoked intense interest in understanding how they interact with their receptors and effecters, Nonetheless, the locations of the receptor and effector binding sites remain poorly characterized, although nearly complete structures of the alpha beta gamma heterotrimeric complex are available, Here we apply evolutionary trace (ET) analysis [Lichtarge, O., Bourne, H. R. & Cohen, F. E. (1996) J. Mol. Biol. 257, 342-358] to propose plausible locations for these sites. On each subunit, ET identifies evolutionarily selected surfaces composed of residues that do not vary within functional subgroups and that form spatial clusters, Four clusters correctly identify subunit interfaces, and additional clusters on G(alpha) point to likely receptor or effector binding sites, Our results implicate the conformationally variable region of G(alpha) in an effector binding role. Furthermore the range of predicted interactions between the receptor and G(alpha beta gamma) is sufficiently limited that we can build a low resolution and testable model of the receptor-G protein complex.