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

Trace amine-associated receptors (TAARs), a G-protein-coupled receptor subclass detecting volatile amines, are co-expressed with odorant receptors in the main olfactory epithelium. While many behaviorally relevant amines are known for olfactory TAARs, the molecular basis of their selectivity for amines of varying lengths and primary/tertiary amines remains unclear. Using mTAAR7e as a model, we combined cAMP accumulation luciferase assays and computational simulations to investigate this issue. Molecular dynamics (MD) simulations and structure-activity relationship analysis established a clear preference for medium-chain, tertiary amines. Optimal steric complementarity within the binding pocket dictates the preference for medium-length alkyl chains like DMHA and DMOA. Site-directed mutagenesis further confirmed the essential role of Asp127 3.32 in anchoring the amine group. Together, these findings offer valuable insights into TAAR ligand selectivity and may advance understanding of TAAR-mediated olfactory and systemic aminergic signaling.