The olfactory system has sophisticated molecular mechanisms for recognizing and discriminating an enormous number of odorants. The detection of odorants in mammals is mediated by several hundreds of olfactory receptors (ORs), which comprise the largest superfamily of G-protein-coupled receptors (GPCRs) in the genome. Because GPCRs are major targets for therapeutic application, ample experimental data and computer modeling studies are available on some GPCRs. However, even though ORs represent approximately one half of all GPCRs, few structural and functional studies have been carried out for ORs. Here, we review recent studies on mechanisms underlying the molecular recognition of a large number of odorants by ORs. A combination of computational and experimental approaches has revealed the odorant-binding site of ORs. Point mutations in the odorant binding site based on the mode of odorant binding resulted in predicted changes in ligand specificity and antagonist activity, demonstrating the validity of the binding site model and indicating that it may be applied to the design of useful ligands for ORs. Understanding the molecular basis for the discriminative power of the olfactory system will also provide insight into how to design agonists or antagonists of GPCRs.
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