Exchanging ligand-binding specificity between a pair of mouse olfactory receptor paralogs reveals odorant recognition principles.

Shuguang Yuan,Slawomir Filipek,Olivia Baud,Horst Pick,Luc Veya,Horst Vogel

doi:10.1038/srep14948

Shuguang Yuan, Slawomir Filipek + Show 4 more

Open Access

https://doi.org/10.1038/srep14948

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Abstract

A multi-gene family of ~1000 G protein-coupled olfactory receptors (ORs) constitutes the molecular basis of mammalian olfaction. Due to the lack of structural data its remarkable capacity to detect and discriminate thousands of odorants remains poorly understood on the structural level of the receptor. Using site-directed mutagenesis we transferred ligand specificity between two functionally related ORs and thereby revealed amino acid residues of central importance for odorant recognition and discrimination of the two receptors. By exchanging two of three residues, differing at equivalent positions of the putative odorant binding site between the mouse OR paralogs Olfr73 (mOR-EG) and Olfr74 (mOR-EV), we selectively changed ligand preference but remarkably also signaling activation strength in both ORs. Computer modeling proposed structural details at atomic resolution how the very same odorant molecule might interact with different contact residues to induce different functional responses in two related receptors. Our findings provide a mechanistic explanation of how the olfactory system distinguishes different molecular aspects of a given odorant molecule, and unravel important molecular details of the combinatorial encoding of odorant identity at the OR level.

Highlights

A multi-gene family of ~1000 G protein-coupled olfactory receptors (ORs) constitutes the molecular basis of mammalian olfaction
The binding of odorants to their ORs located on the cilia of specialized olfactory sensory neurons (OSN) in the nasal, olfactory epithelium represents the primary event of odor detection initiating a neuronal response that triggers the perception of a smell in the brain[8,9]
In order to explain the results of our functional assays on a structural level by localizing trans-membrane domains (TM) residues, which might define odorant specificity in Olfr[73] and Olfr[74] we used homology modelling and molecular dynamics (MD) simulations based on the atomic structure of the activated β -2 adrenergic receptor[24]

Summary

Introduction

A multi-gene family of ~1000 G protein-coupled olfactory receptors (ORs) constitutes the molecular basis of mammalian olfaction. Screening a library of 270 compounds we have found jasmone as a new potent agonist specific only to Olfr[74] and two less potent odorants, rose oxide and nootkatone, activating both paralogous ORs with different efficacies.

Results

Conclusion