Achievement in Olfaction: Scientists Produces First 3D Image of Odor Molecule Activating Human Odorant Receptor

Tuesday - May 2 2023, 07:16 UTC - 1 year ago

UC San Francisco scientists have made a significant breakthrough, producing the first 3D image of how an odor molecule activates a human odorant receptor. This advancement has far-reaching implications for fragrances, food science, and more.

Scientists from UC San Francisco (UCSF) have accomplished a significant breakthrough in our understanding of olfaction by producing the first 3D image at the molecular level of how an odor molecule activates a human odorant receptor. This achievement is a crucial advancement toward unraveling the intricacies of the sense of smell.

The findings, published in the journal Nature, are expected to rekindle interest in the science of smell, with far-reaching implications for fragrances, food science, and more. Odorant receptors, which are proteins situated on the surface of olfactory cells and bind to odor molecules, constitute half of the most diverse and extensive family of receptors in our bodies. A more comprehensive comprehension of them lays the groundwork for novel discoveries in a variety of biological processes.

"This has been a huge goal in the field for some time," said Aashish Manglik, MD, Ph.D., 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.

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, Ph.D., 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, Ph.D., 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.

"We made this happen by overcoming several technical impasses that have stifled the field before," said Billesbøelle, who was a postdoctoral fellow in the lab when he made the discovery.