How do olfactory receptors discriminate scents? 🌸

To advance the understanding of olfaction, visualizing the binding of odorants to olfactory receptors remains a challenge.

By resolving the structure of olfactory receptors, a Franco-American team of scientists has shown how they bind to odorant molecules and the associated activation mechanisms*. Results published in the journal Nature could find applications in perfumery, the food industry, and even the pharmaceutical sector.


Our sense of smell relies on the interaction between the odorant molecules we inhale and proteins known as "olfactory receptors." These receptors have long been black boxes, with their three-dimensional atomic-scale structure unknown to us. However, to improve our understanding of olfaction, visualizing how the odorant molecule binds to the receptor is an essential step.

In 2023, the very first structure of a human olfactory receptor was published in Nature. It was that of a class I receptor, a category that accounts for 16% of our receptors specialized in detecting carboxylic acids**.

The structure of class II olfactory receptors, which represent 84% of our receptors and are used to detect almost all the odorant molecules we perceive, remained unknown until now. For a very simple reason: in humans and other mammals, these receptors are not expressed (produced) in sufficient quantities for their structure to be elucidated. This low expression has long hindered structural determination of olfactory receptors, making their study particularly challenging until today.

To overcome this hurdle, scientists from the Institut de Chimie des Substances Naturelles (CNRS) and Duke University constructed ***consensus sequences of olfactory receptors from the complete set of sequences found within a subfamily of receptors present in the human nose.


To do this, they selected, for each of the 350 positions, the most frequently observed amino acid across all receptors in the subfamily. Produced in sufficient quantities, these consensus receptors, serving as "models" of an olfactory receptor family, allowed them to obtain four new experimental structures of olfactory receptors, including three structures of class II receptors bound to various odorant molecules.

These structures reveal that class I and class II olfactory receptors use distinct modes of binding to odorant molecules and different activation mechanisms. Class I receptors employ a simple activation mechanism. A single amino acid, present in all receptors of this class, is involved in detecting carboxylic acids.

In contrast, class II receptors, which bind to much more varied molecules, require several amino acids distributed throughout their cavity to detect these diverse odorant molecules.

These findings will have an impact on our understanding of scent perception and may find applications in the fields of perfumery and food production. But that's not all. They may also interest pharmacologists, as some of these olfactory receptors are expressed in various types of cells outside our olfactory system and appear to play a role in the proliferation of certain cancers.

Notes:

* An activation mechanism associated with an olfactory receptor describes the process through which an odorant molecule binds to the receptor, triggering a cascade of reactions within the sensory neuron that ultimately leads to the perception of a scent.

** Carboxylic acids are R-COOH groups found in cheese, coconut, certain fruits, vinegar, and many animal or vegetable oils.

*** Each olfactory receptor consists of a sequence of about 350 amino acids.

Author: CCdM

Reference:

Engineered odorant receptors illuminate the basis of odour discrimination
Nature 2024 - https://www.nature.com/articles/s41586-024-08126-0
DOI: 10.1038/s41586-024-08126-0