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

Affiliations
  • 1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
  • 2Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, NG7 2RD, UK.
  • 3Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
  • 4Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, 1218 S 5th Ave, Monrovia, CA, 91016, USA.
  • 5Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
  • 6Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • 7Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK. sw644@cam.ac.uk.
  • 8Cambridge Institute for Medical Research, Keith Peters Building, Biomedical Campus, Hills Rd, Cambridge, CB2 0XY, UK. sw644@cam.ac.uk.
  • 9EMBL’s European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK. sw644@cam.ac.uk.
  • 10MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. cgt@mrc-lmb.cam.ac.uk.

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August 30, 2024

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 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.

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