Conformational Sensing by a Mammalian Olfactory Receptor.

Area of Science:

• Olfactory receptor function
• G protein-coupled receptor superfamily
• Chemosensation

Background:

• Mammalian olfaction relies on hundreds of olfactory receptors (ORs), a class of G protein-coupled receptors.
• Odorant molecules with rotatable bonds pose challenges to traditional shape-based odor recognition models.
• Understanding how odorant conformation influences receptor interaction is key to deciphering the sense of smell.

Purpose of the Study:

• To investigate whether olfactory receptors (ORs) can differentiate between various conformations of the same odorant molecule.
• To determine if the conformational flexibility of an odorant influences its interaction with a specific OR.
• To explore the mechanism of odorant-receptor binding beyond simple stereochemical matching.

Main Methods:

• Utilized calcium imaging to monitor signal transduction in mouse sensory neurons.
• Focused on the mouse aldehyde olfactory receptor, Olfr2.
• Conformationally restricted the carbon chain of the odorant octanal to study its different spatial arrangements.

Main Results:

• Demonstrated that the spatial positioning of octanal's C7 and C8 carbons relative to its aldehyde group dictates its activity.
• Observed that octanal can act as an agonist, partial agonist, or antagonist depending on its conformation.
• Provided evidence that odorants can actively modulate ORs through their intrinsic conformational states.

Conclusions:

• Odorant conformation plays a critical role in determining olfactory receptor response, challenging purely shape-based models.
• The findings suggest a dynamic interaction where odorants utilize their conformational flexibility to signal to olfactory receptors.
• This mechanism offers a novel perspective on olfactory coding, drawing parallels to photon-induced conformational changes in rhodopsin.