Agonists for 13 Trace
Amine-Associated Receptors Provide
Insight into the Molecular Basis of Odor Selectivity
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Abstract
Trace amine-associated receptors (TAARs) are vertebrate
olfactory
receptors. However, ligand recognition properties of TAARs remain
poorly understood, as most are “orphan receptors” 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 <i>Taar7</i> 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 β<sub>2</sub> 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