The variable and conserved interfaces of modeled olfactory receptor proteins

The accumulation of hundreds of olfactory receptor (OR) sequences, along wi th the recent availability of detailed models of other G-protein-coupled re ceptors, allows us to analyze the OR amino acid variability patterns in a s tructural context. A Fourier analysis of 197 multiply aligned olfactory rec eptor sequences showed an alpha-helical periodicity in the variability prof ile. This was particularly pronounced in the more variable transmembranal s egments 3, 4, and 5. Rhodopsin-based homology modeling demonstrated that th e inferred variable helical faces largely point to the interior of the rece ptor barrel. We propose that a set of 17 hypervariable residues. which poin t to the barrel interior and are more extracellular ly disposed, constitute the odorant complementarity determining regions. While 12 of these residue s coincide with established ligand-binding contact postions in other G-prot ein-coupled receptors, the rest are suggested to form an olfactory-unique a spect of the binding pocket. Highly conserved olfactory receptor-specific s equence motifs, found in the second and third intracellular loops, may comp rise the G-protein recognition epitope. The prediction of olfactory recepto r functional sites provides concrete suggestions of site-directed mutagenes is experiments for altering ligand and G-protein specificity.