Making sense of scents: Deciphering our sense of smell

 Breaking a longstanding impasse in our understanding of olfaction, scientists at UC San Francisco (UCSF) have created the first molecular-level, 3D picture of how an odor molecule activates a human odorant receptor, a crucial step in deciphering the sense of smell.

The findings, appearing online March 15, 2023, in Nature, are poised to reignite interest in the science of smell with implications for fragrances, food science, and beyond. Odorant receptors -- proteins that bind odor molecules on the surface of olfactory cells -- make up half of the largest, most diverse family of receptors in our bodies; A deeper understanding of them paves the way for new insights about a range of biological processes.

"This has been a huge goal in the field for some time," said Aashish Manglik, MD, PhD, an associate professor of pharmaceutical chemistry and a senior author of the study. The dream, he said, is to map the interactions of thousands of scent molecules with hundreds of odorant receptors, so that a chemist could design a molecule and predict what it would smell like.

"But we haven't been able to make this map because, without a picture, we don't know how odor molecules react with their corresponding odor receptors," Manglik said.

A Picture Paints the Scent of Cheese

Smell involves about 400 unique receptors. Each of the hundreds of thousands of scents we can detect is made of a mixture of different odor molecules. Each type of molecule may be detected by an array of receptors, creating a puzzle for the brain to solve each time the nose catches a whiff of something new.

"It's like hitting keys on a piano to produce a chord," said Hiroaki Matsunami, PhD, professor of molecular genetics and microbiology at Duke University and a close collaborator of Manglik. Matsunami's work over the past two decades has focused on decoding the sense of smell. "Seeing how an odorant receptor binds an odorant explains how this works at a fundamental level."

To create that picture, Manglik's lab used a type of imaging called cryo-electron microscopy (cryo-EM), that allows researchers to see atomic structure and study the molecular shapes of proteins. But before Manglik's team could visualize the odorant receptor binding a scent molecule, they first needed to purify a sufficient quantity of the receptor protein.

Odorant receptors are notoriously challenging, some say impossible, to make in the lab for such purposes.

The Manglik and Matsunami teams looked for an odorant receptor that was abundant in both the body and the nose, thinking it might be easier to make artificially, and one that also could detect water-soluble odorants. They settled on a receptor called OR51E2, which is known to respond to propionate -- a molecule that contributes to the pungent smell of Swiss cheese.

But even OR51E2 proved hard to make in the lab. Typical cryo-EM experiments require a milligram of protein to produce atomic-level images, but co-first author Christian Billesbøelle, PhD, a senior scientist in the Manglik Lab, developed approaches to use only 1/100th of a milligram of OR51E2, putting the snapshot of receptor and odorant within reach.

Source: ScienceDaily