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

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 G<sub>s</sub> 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, Trp<sup>6.48</sup>.

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Journal
Nature Communications
Published
2024-08-30
DOI
https://doi.org/10.1038/s41467-024-51793-w
Citations
10
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
1.87

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article

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

Dmitry B. Veprintsev, Eline J. Koers, Patricia C. Edwards, Filippo Mancia et al.
10 citations
Nature Communications
Receptor Mechanisms and Signaling
1.87
article

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

Dmitry B. Veprintsev, Eline J. Koers, Patricia C. Edwards, Filippo Mancia, Nagarajan Vaidehi, Anastasiia Gusach, Ning Ma, Fanglu Huang, Elizaveta Mukhaleva, Christopher G. Tate, Qingchao Chen, Armin Nikpour Khoshgrudi, Yang Lee, Jonathan Kim, Simone Weyand
article en
10 citations

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 G<sub>s</sub> 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, Trp<sup>6.48</sup>.

Nature CommunicationsVol. 15(1)
European Bioinformatics Institute (GB), University of Nottingham (GB), MRC Laboratory of Molecular Biology (GB), University of Cambridge (GB), Columbia University Irving Medical Center (US), Royal Papworth Hospital (GB), City of Hope (US), Institute for Medical Research (MY), Beckman Research Institute, University of Birmingham (GB)
Wellcome, Wellcome Trust, Isaac Newton Trust, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 14%
Receptor Mechanisms and Signaling
1.87
DOIOpen Access PDFOpenAlex
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