Smelling Molecular Conformations

What molecular features can olfactory receptors recognize? Functional groups—such as sulfur-based ones—certainly contribute to the smell of a compound, but the stereochemistry of an odorant can also play a role. The molecular details of the function of olfactory receptors in mammals are unknown due to a lack of X-ray structures of the receptors. Understanding how the receptors respond to different conformers could help to explain how some natural products produce their distinctive odors and how small variations in a compound’s carbon framework can change its smell.

Kevin Ryan, City University of New York, and colleagues have investigated whether an olfactory receptor can respond differently to different odorant conformations. Starting from the fragrant aldehyde octanal, they synthesized analogs locking the C7 and C8 carbons in different spatial relationships to the aldehyde group (pictured above, C7 and C8 = Et) by adding C–C bonds along the chain. The team then used calcium imaging (a microscopy technique based on fluorescent indicators) to monitor the signals in sensory neurons expressing a mouse olfactory receptor for aldehydes, called Olfr2, in the presence of these analogs.

The researchers found that each analog binds to the Olfr2 aldehyde receptor, but produces a different response in the sensory neurons expressing the receptor. Octanal is an Olfr2 agonist, i.e., it binds and activates the receptor. One of the spatial analogs is an even more potent ligand than octanal (pictured in green). A second analog shows evidence of being a partial agonist (pictured in yellow), and the third functions as an antagonist (pictured in red), i.e., it blocks the receptor action.

The results show that an olfactory receptor senses the conformational repertoire of a bound odorant, just as it can sense functional groups. Different conformations contribute differently to what is likely a combined response. Restricting the bond rotations of flexible odorants could be used to tune ligand potency, and thus, cause changes in their odor.