Agonists for 13 Trace Amine-Associated Receptors Provide Insight into the Molecular Basis of Odor Selectivity

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• 作者：David M. Ferrero ; Daniel Wacker ; Miguel A. Roque ; Maude W. Baldwin ; Raymond C. Stevens ; Stephen D. Liberles
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：July 20, 2012
• 年：2012
• 卷：7
• 期：7
• 页码：1184-1189
• 全文大小：508K
• 年卷期：v.7,no.7(July 20, 2012)
• ISSN：1554-8937

文摘

Trace amine-associated receptors (TAARs) are vertebrate olfactory receptors. However, ligand recognition properties of TAARs remain poorly understood, as most are 鈥渙rphan receptors鈥?without known agonists. Here, we identify the first ligands for many rodent TAARs and classify these receptors into two subfamilies based on the phylogeny and binding preference for primary or tertiary amines. Some mouse and rat orthologs have similar response profiles, although independent Taar7 gene expansions led to highly related receptors with altered ligand specificities. Using chimeric TAAR7 receptors, we identified an odor contact site in transmembrane helix III that functions as a selectivity filter. Homology models based on the 尾₂ adrenergic receptor structure indicate spatial proximity of this site to the ligand. Gain-of-function mutations at this site created olfactory receptors with radically altered odor recognition properties. These studies provide new TAAR ligands, valuable tools for studying receptor function, and general insights into the molecular pharmacology of G protein-coupled receptors.