Journal Article

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

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

2024

Overview

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 s 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 6.48 . Smells are detected in the nose by odorant molecules binding to a specific G protein-coupled receptor on the cell surface. Here, authors have determined the atomic structure of a receptor bound to an odorant molecule that showing how the odorant binds and activates the receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 147/28 / 631/45/612/194 / 631/535/1258/1259 / 82/80 / 82/83 / 96 / 96/33 / Amino acids / Animals / Aspartic acid / Atomic structure / Binding Sites / Cell activation / Cell surface / Cell surface receptors / Cryoelectron Microscopy / Dopamine / G protein-coupled receptors / HEK293 Cells / Humanities and Social Sciences / Humans / Hydrophobicity / Ligands / Mice / Molecular dynamics / Molecular Dynamics Simulation / Molecular structure / multidisciplinary / Mutagenesis / Odorant receptors / Odorants / Odorants - analysis / Odors / Protein Binding / Protein structure / Proteins / Receptors / Receptors (physiology) / Receptors, G-Protein-Coupled - chemistry / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Receptors, Odorant - chemistry / Receptors, Odorant - genetics / Receptors, Odorant - metabolism / Recognition / Residues / Science / Science (multidisciplinary) / Serotonin / Structure-odor relationships