2-SITE BINDING OF C5A BY ITS RECEPTOR - AN ALTERNATIVE BINDING PARADIGM FOR G-PROTEIN-COUPLED RECEPTORS

The guanine nucleotide-binding protein-coupled receptor superfamily bi nds a vast array of biological messengers including lipids, odorants, catecholamines, peptides, and proteins. While some small molecules bin d to these receptors at a single interhelical site, we find that the b inding domain on the receptor for the inflammatory protein C5a is more complex and consists of two distinct subsites. This more elaborate mo th appears to be an evolutionary adaptation of the simpler paradigm to which a second interaction site has been added in the receptor N term inus. Surprisingly, occupation of only one of the subsites is required for receptor activation. The two-site motif is not unique to the C5a receptor but appears to be widely used by the superfamily to accommoda te macromolecular ligands.