Our sense of smell allows us to navigate a vast space of chemically diverse odor molecules. This task is accomplished through the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome. How odorant receptors recognize odorants remains unclear.

In a new study, scientists at UC San Francisco (UCSF) provide mechanistic insight into how an odorant binds to a human odorant receptor. They have created the first molecular-level 3D image of how an odorant molecule activates a human odorant receptor.

Odor receptors are proteins that bind odor molecules on the surface of olfactory cells. It created the largest, most diverse family of receptors in our body. Understanding those can provide new insights into a range of biological processes.

Smell involves 400 different receptors. The hundreds of thousands of odors we can detect are each composed of a unique mixture of odor molecules. Every time the nose picks up a scent of something new, the brain has to solve a riddle, as each type of molecule can be detected by different receptors.

Hiroaki Matsunami, Ph.D., a professor of molecular genetics and microbiology at Duke University and a close associate of Manglik, said: “It’s like hitting keys on a piano to produce a chord. Seeing how an odorant receptor binds to an odorant explains how this works on a fundamental level.”

Scientists used cryo-electron microscopy (cryo-EM) to create the image. With Cryo-EM we can see the atomic structure and study the molecular shapes of proteins. But before the binding of the odorant receptor to an odorant became visible, scientists first had to purify a sufficient amount of the receptor protein.

Scientists searched for an odor receptor that is abundant in the body and nose. They thought it might be easier to make a synthetic version of an odorant receptor and one that could also detect water-soluble odorants. So they chose the OR51E2 receptor because it has been shown to react with propionate, a compound involved in the strong flavor of Swiss cheese.

But even producing OR51E2 in a lab proved challenging. Typical cryo-EM experiments require a milligram of protein to have atomic-level images. Yet scientists developed approaches to use as little as 1/100th of a milligram of OR51E2, putting the receptor and odorant snapshot within reach.

Co-first author Christian Billesbølle, Ph.D., a senior scientist in the Manglik Lab, said: “We made this possible by overcoming several technical deadlocks that have stifled the field for a long time. By doing that, we were able to catch the first glimpse of an odorant connecting to a human odorant receptor the moment an odor is detected.

Through an exact match between odorant and receptor, this molecular snapshot showed that propionate attaches tightly to OR51E2 to bind to it. The discovery is consistent with the olfactory system’s function as a sentinel for danger.

Propionate helps give Swiss cheese its deep, nutty aroma, but it has a much less enticing scent of its own.

Aashish Manglik, MD, Ph.D., an associate professor of pharmaceutical chemistry, said: “This receptor is laser-targeted to detect propionate and may have evolved to help detect when food has gone bad. Receptors for pleasant smells such as menthol or caraway could instead interact more loosely with odorants.

Then scientists determined how propionate activates this receptor. To do this, they performed computer simulations and filmed how OR51E2 is turned on by propionate. The simulations help them understand how propionate causes a shape change in the receptor at the atomic level.

Quantitative biologist Nagarajan Vaidehi, Ph.D., at the City of Hope, said: “We performed computer simulations to understand how propionate causes a shape change in the receptor at the atomic level. These shape changes play a critical role in how the olfactory receptor initiates the cell signaling process that leads to our sense of smell.”

The team is currently developing more effective methods to investigate additional odorant-receptor pairs and understand the non-olfactory biology associated with the receptors, which have been linked to prostate cancer and the production of serotonin in the gut.

Manglik envisions a future where new scents could be designed based on an understanding of how a chemical’s shape leads to a perceptual experience, similar to how pharmaceutical chemists today design drugs based on the atomic shapes of disease-causing proteins.

Magazine reference:

  1. Billesbølle, CB, de March, CA, van der Velden, WJC et al. Structural basis of odor recognition by a human odorant receptor. Nature (2023). DOI: 10.1038/s41586-023-05798-y