Structural insights on the ligand selectivity of the mouse trace amine-associated receptor TAAR7e

Abstract

Trace amine-associated receptors (TAARs), a subclass of G protein-coupled receptors involved in detecting volatile amines, are co-expressed with odorant receptors in the main olfactory epithelium. Although many behaviorally relevant amines have been identified for olfactory TAARs, the molecular mechanisms underlying their selectivity for amines with varying carbon chain lengths and degrees of amine substitution remain unclear. In this study, we used mTAAR7e as a model to investigate these mechanisms. Homology modeling revealed a conserved ligand-binding pocket, supported by sequence-structure covariance analysis across TAARs. Structure-activity relationship profiling revealed key chemical determinants integral to mTAAR7e-mediated odorant recognition and provided, for the first time, a structural explanation for its selective preference toward longer carbon chains and tertiary amines. Computationally predicted interactions between mTAAR7e and the representative ligand N,N-dimethylcyclohexylamine (DMCHA) were validated through site-directed mutagenesis. Furthermore, conformational dynamics of mTAAR7e during receptor activation were characterized, providing insights into activation-related structural rearrangements. Together, these findings offer novel insights into the molecular logic of TAAR ligand selectivity and may advance our understanding of how TAARs mediate both olfactory and systemic aminergic signaling.