TY - JOUR
T1 - A molecular basis for odorant recognition
T2 - Olfactory receptor pharmacology
AU - Katada, Sayako
AU - Touhara, Kazushige
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004
Y1 - 2004
N2 - Olfactory receptors (ORs) comprise the largest super-family of rhodopsin-like G-protein coupled receptors (GPCR) that involve the recognition and discrimination of thousands of odorants. We recently succeeded in functional reconstitution of mouse ORs in mammalian cell lines and provided molecular evidence that structurally-related ORs recognized overlapping sets of odorants with distinct ligand specificities. Here we show that mOR-EG, a mouse olfactory receptor that was isolated from a eugenol-responsive cell, recognizes 22 different odorants with EC50values ranging from a few μ M to several hundred μ M. We constructed a molecular model of mOR-EG using the recent atomic-level structure of bovine rhodopsin. Site-directed mutations were introduced in a potential ligand-binding pocket based on computational ligand-docking simulation. Mutations of some amino acid residues in TM3, TM5, and TM6 dramatically affected the EC50value of eugenol in Ca 2+ imaging. Finally, we succeeded in rational receptor design with predicted ligand specificity by introducing point mutations in the binding site, confirming the accuracy of the binding site mapping. The current studies also help understand mechanisms underlying molecular recognition by GPCRs, with implications for therapeutic application.
AB - Olfactory receptors (ORs) comprise the largest super-family of rhodopsin-like G-protein coupled receptors (GPCR) that involve the recognition and discrimination of thousands of odorants. We recently succeeded in functional reconstitution of mouse ORs in mammalian cell lines and provided molecular evidence that structurally-related ORs recognized overlapping sets of odorants with distinct ligand specificities. Here we show that mOR-EG, a mouse olfactory receptor that was isolated from a eugenol-responsive cell, recognizes 22 different odorants with EC50values ranging from a few μ M to several hundred μ M. We constructed a molecular model of mOR-EG using the recent atomic-level structure of bovine rhodopsin. Site-directed mutations were introduced in a potential ligand-binding pocket based on computational ligand-docking simulation. Mutations of some amino acid residues in TM3, TM5, and TM6 dramatically affected the EC50value of eugenol in Ca 2+ imaging. Finally, we succeeded in rational receptor design with predicted ligand specificity by introducing point mutations in the binding site, confirming the accuracy of the binding site mapping. The current studies also help understand mechanisms underlying molecular recognition by GPCRs, with implications for therapeutic application.
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U2 - 10.1254/fpj.124.201
DO - 10.1254/fpj.124.201
M3 - Review article
C2 - 15467253
AN - SCOPUS:7044253441
VL - 124
SP - 201
EP - 209
JO - Folia Pharmacologica Japonica
JF - Folia Pharmacologica Japonica
SN - 0015-5691
IS - 4
ER -