Molecular determinants of ligand selectivity in a vertebrate odorant receptor.
The identification of the chemical structure of an odorant by the vertebrate olfactory system is thought to occur through the combinatorial activity from multiple receptors, each tuned to recognize different chemical features. What are the molecular determinants underlying the selectivity of individual odorant receptors for their cognate ligands? To address this question, we performed molecular modeling and site-directed mutagenesis on the ligand-binding region of two orthologous amino acid odorant receptors belonging to the "C family" of G-protein-coupled receptors in goldfish and zebrafish. We identified the critical ligand-receptor interactions that afford ligand binding as well as selectivity for different amino acids. Moreover, predictions regarding binding pocket structure allowed us to alter, in a predictable manner, the receptor preferences for different ligands. These results reveal how this class of odorant receptor has evolved to accommodate ligands of varying chemical structure and further illuminate the molecular principles underlying ligand recognition and selectivity in this family of chemosensory receptors.
Luu
Percy
P
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720-3200, USA.
Acher
Francine
F
Bertrand
Hugues-Olivier
HO
Fan
Jinhong
J
Ngai
John
J
D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000032:analysis; D002460:Cell Line / Q000737:chemistry; D018076:DNA, Complementary / Q000235:genetics; D015723:Gene Library; D005998:Glycine / Q000737:chemistry; D006054:Goldfish / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000166:cytology; D008024:Ligands; D008958:Models, Molecular; D009010:Monte Carlo Method; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018035:Receptors, Odorant / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000235:genetics
D000596:Amino Acids; D018076:DNA, Complementary; D008024:Ligands; D018035:Receptors, Odorant; D011993:Recombinant Fusion Proteins; D029961:Zebrafish Proteins; C500969:gprc6a protein, zebrafish; D001120:Arginine; D002118:Calcium; D005998:Glycine