Unlocking New Fragrances – A Game-Changing Breakthrough in the Fragrance World

The first molecular images of olfaction have opened the door to the creation of new scents.

Scientists at UC San Francisco (UCSF) have achieved a major breakthrough in our understanding of smell by creating the first molecular-level 3D image of how an odor molecule activates a human olfactory receptor. This achievement is a major breakthrough in unraveling the complexity of the sense of smell.

Findings published in the journal NatureIt is expected to rekindle interest in the science of fragrance, with implications for fragrances, food science, and more. Olfactory receptors, which are proteins on the surface of olfactory cells that bind to odor molecules, make up half of the most diverse and extensive family of receptors in our body. A wider understanding of them lays the foundation for new discoveries in various biological processes.

“This has been a huge goal in the field for some time,” said Aashish Manglik, MD, Ph.D., associate professor of pharmaceutical chemistry and 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 can design a molecule and predict how it will smell.

“But we haven’t been able to create this map because without an image, we don’t know how the odor molecules interact with the corresponding odor receptors,” Manglik said.

The picture paints the smell 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 can be detected by a series of receptors, creating a puzzle for the brain to solve every time the nose detects something new.

“It’s like pressing piano keys to make a chord,” said Hiroaki Matsunami, Ph.D., a professor of molecular genetics and microbiology at Duke University and a close collaborator of Manglik. For the past two decades, Matsunami’s work has focused on deciphering olfaction. “Seeing how an odorant receptor binds to an odorant explains how it works at a fundamental level.”

To create this image, Manglik’s lab used a type of imaging called cryo-electron microscopy (cryo-EM), which allows researchers to see the structure of atoms and study the molecular shapes of proteins. But before Manglik’s team could visualize an olfactory receptor binding to an odor molecule, they first had to purify sufficient amounts of the receptor protein.

Olfactory receptors are very difficult, some say impossible, to make in the laboratory for such purposes.

Manglik and Matsunami’s 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 could also detect water-soluble odors. They settled on a receptor called OR51E2, which is known to respond to propionate, the molecule that contributes to the sharp smell of Swiss cheese.

But even OR51E2 proved difficult to make in the laboratory. Typical cryo-EM experiments require a milligram of protein to produce atomic-level images, but co-author Christian Billesbøelle, Ph.D., a senior scientist in the Manglik Lab, developed approaches to use just 1/100th of a milligram of OR51E2, providing a snapshot of capture and smell.

“We achieved this by overcoming several technical bottlenecks that have stifled the field for a long time,” said Billesbeelle. “This allowed us to observe, for the first time, an odor that binds to the human olfactory receptor at the exact moment the odor is detected.”

This molecular snapshot showed that propionate adheres tightly to OR51E2 through a highly specific odorant and receptor. The discovery highlights one of the olfactory system’s duties as a danger watchdog.

Although propionate contributes to the rich, nutty flavor of Swiss cheese, the smell itself is much less appetizing.

“This receptor targets the laser to try to sense propionate, and it may have evolved to help detect when food has gone bad,” Manglik said. He speculated that receptors that produce pleasant odors, such as menthol or cumin, might interact more freely with odorants.

Just a Whiff

Along with using a large number of receptors at once, another interesting quality of smell is our ability to detect small amounts of odors that may come and go. To investigate how propionate activates this receptor, the collaboration enlisted quantitative biologist Nagarajan Vaidehi, Ph.D. from the City of Hope, who used physics-based methods to model and make movies of how propionate turns on OR51E2.

“We performed computer simulations to understand how propionate causes receptor shape changes at the atomic level,” Vaidehi said. “These shape changes are critical to how the odorant receptor initiates the cellular signaling process that leads to our sense of smell.”

The team is now developing more efficient methods to study other olfactory-receptor pairs and understand the neo-olfactory biology associated with receptors linked to prostate cancer and intestinal serotonin release.

Manglik envisions a future where new fragrances can be designed based on understanding how a chemical’s shape creates a perceptual experience, unlike how pharmaceutical chemists today design drugs based on the atomic shapes of disease-causing proteins.

“We’ve dreamed of solving this problem for years,” he said. “Now we have the first finger, the first insight into how odor molecules bind to our odor receptors. For us, this is just the beginning.”

Reference: “Structural Basis of Odor Recognition by the Human Odorant Receptor” by Kristians B. Billesbælle, Claire A. de Marta, Wijnand J.K. van der Velden, Ning Ma, Jeevan Tewari, Claudia Llinas del Torrenta, Linus Li, Brian Faust, Nagarajan Vaidehi, Hiroaki Matsunami, and Aashish Manglik, March 15, 2023, Nature.
DOI: 10.1038/s41586-023-05798-y

Funding: This work was funded by the National Institutes of Health and the UCSF Program for Biomedical Breakthrough, funded in part by the Sandler Foundation. The cryo-EM facility at UCSF is supported in part by NIH grants. For other funding, please see the paper.