POSITIVE SELECTION MOMENTS IDENTIFY POTENTIAL FUNCTIONAL RESIDUES IN HUMAN OLFACTORY RECEPTORS

Correlated mutation analysis and molecular models of olfactory recepto rs have provided evidence that residues in the transmembrane domains f orm a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha- helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferent ially affected by positive selection and are thus likely to interact w ith odor ligands. The results suggest that residue 622, which is commo nly a serine or threonine, could form critical H-bonds. In some recept ors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of the se residues is further supported by site-directed mutagenesis in the b eta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutag enesis.