EVOLUTIONARILY CONSERVED G(ALPHA-BETA-GAMMA) BINDING SURFACES SUPPORTA 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 understandin g how they interact with their receptors and effecters, Nonetheless, t he locations of the receptor and effector binding sites remain poorly characterized, although nearly complete structures of the alpha beta g amma 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 surface s composed of residues that do not vary within functional subgroups an d that form spatial clusters, Four clusters correctly identify subunit interfaces, and additional clusters on G(alpha) point to likely recep tor or effector binding sites, Our results implicate the conformationa lly variable region of G(alpha) in an effector binding role. Furthermo re the range of predicted interactions between the receptor and G(alph a beta gamma) is sufficiently limited that we can build a low resoluti on and testable model of the receptor-G protein complex.