Abstract
The trace amine-associated receptor 1 (TAAR 1) is an aminergic G protein-coupled receptor (GPCR) potently activated by 3-iodothyronamine (1), an endogenous derivative of thyroid hormone. Structure-activity relationship studies on 1 and related agonists showed that the rat and mouse species of TAAR 1 accommodated structural modifications and functional groups on the ethylamine portion and the biaryl ether moiety of the molecule. However, the two receptors clearly exhibited distinct, species-specific ligand preferences despite being remarkably similar with 93% sequence similarity. In this study, we generated single and double mutants of rat and mouse TAAR 1 to probe the molecular recognition of agonists and the underlying basis for the ligand selectivity of rat and mouse TAAR 1. Key, nonconserved specificity determinant residues in transmembranes helices 4 and 7 within the ligand binding site appear to be the primary source of a number of the observed ligand preferences. Residue 7.39 in transmembrane 7 dictated the preference for a β-phenyl ring, while residue 4.56 in transmembrane 4 was partially responsible for the lower potency of 1 and tyramine for the mouse receptor. Additionally, 1 and tyramine were found to have the same binding mode in rat TAAR 1 despite structure- activity relationship data suggesting the possibility of each molecule having different binding orientations. These findings provide valuable insights into the critical binding site residues involved in the ligand-receptor interaction that can influence compound selectivity and functional activity of aminergic GPCRs.
Original language | English (US) |
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Pages (from-to) | 209-220 |
Number of pages | 12 |
Journal | ACS chemical biology |
Volume | 4 |
Issue number | 3 |
DOIs | |
State | Published - Mar 20 2009 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine