Molecular recognition of an odorant by the murine trace amine-associated receptor TAAR7f

Anastasiia Gusach, Yang Lee, Armin Nikpour Khoshgrudi, Elizaveta Mukhaleva, Ning Ma, Eline J. Koers, Qingchao Chen, Patricia C. Edwards, Fanglu Huang, Jonathan Kim, Filippo Mancia, Dmitry B. Veprintsev, Nagarajan Vaidehi, Simone N. Weyand () and Christopher G. Tate ()
Additional contact information
Anastasiia Gusach: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Yang Lee: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Armin Nikpour Khoshgrudi: University of Birmingham and University of Nottingham
Elizaveta Mukhaleva: Beckman Research Institute of the City of Hope
Ning Ma: Beckman Research Institute of the City of Hope
Eline J. Koers: University of Birmingham and University of Nottingham
Qingchao Chen: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Patricia C. Edwards: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Fanglu Huang: University of Cambridge
Jonathan Kim: Columbia University Irving Medical Center
Filippo Mancia: Columbia University Irving Medical Center
Dmitry B. Veprintsev: University of Birmingham and University of Nottingham
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Simone N. Weyand: University of Cambridge
Christopher G. Tate: MRC Laboratory of Molecular Biology, Francis Crick Avenue

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract There are two main families of G protein-coupled receptors that detect odours in humans, the odorant receptors (ORs) and the trace amine-associated receptors (TAARs). Their amino acid sequences are distinct, with the TAARs being most similar to the aminergic receptors such as those activated by adrenaline, serotonin, dopamine and histamine. To elucidate the structural determinants of ligand recognition by TAARs, we have determined the cryo-EM structure of a murine receptor, mTAAR7f, coupled to the heterotrimeric G protein Gs and bound to the odorant N,N-dimethylcyclohexylamine (DMCHA) to an overall resolution of 2.9 Å. DMCHA is bound in a hydrophobic orthosteric binding site primarily through van der Waals interactions and a strong charge-charge interaction between the tertiary amine of the ligand and an aspartic acid residue. This site is distinct and non-overlapping with the binding site for the odorant propionate in the odorant receptor OR51E2. The structure, in combination with mutagenesis data and molecular dynamics simulations suggests that the activation of the receptor follows a similar pathway to that of the β-adrenoceptors, with the significant difference that DMCHA interacts directly with one of the main activation microswitch residues, Trp6.48.

Date: 2024
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DOI: 10.1038/s41467-024-51793-w

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