The first molecular-level, 3D picture of an odor molecule

Making sense of scents.


Our sense of smell enables us to navigate a vast space of chemically diverse odor molecules. This task is accomplished by 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 picture of how an odor molecule activates a human odorant receptor.

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

400 different receptors are involved in smell. The hundreds of thousands of scents we can detect are each composed of a unique blend of odor molecules. Every time the nose picks up a smell of anything new, the brain has to solve a riddle since each type of molecule may be detected by various receptors.

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

Scientists used cryo-electron microscopy (cryo-EM) to create the picture. Cryo-EM allows us to see the atomic structure and study the molecular shapes of proteins. But before visualizing the odorant receptor binding to an odorant, scientists first needed to purify a sufficient quantity of the receptor protein.

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

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

Co-first author Christian Billesbølle, Ph.D., a senior scientist in the Manglik Lab, said“We made this happen by overcoming several technical impasses that have stifled the field for a long time. Doing that allowed us to catch the first glimpse of an odorant connecting with a human odorant receptor at the very moment a scent is detected.”

Via an exact match between odorant and receptor, this molecular snapshot demonstrated that propionate clings firmly 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 far less enticing smell on its own.

Aashish Manglik, MD, Ph.D., an associate professor of pharmaceutical chemistry, said, “This receptor is laser-focused on trying to sense propionate and may have evolved to help detect when food has gone bad. Receptors for pleasing smells like menthol or caraway might instead interact more loosely with odorants.”

Next, scientists determined how propionate activates this receptor. To do so, they performed computer simulations and made movies of how OR51E2 is turned on by propionate. The simulations help them understand how propionate causes a shape change in the receptor at an 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 an atomic level. These shape changes play a critical role in how the odorant receptor initiates the cell signaling process leading to our sense of smell.”

The team is currently creating more effective methods to explore additional odorant-receptor pairs and comprehend the non-olfactory biology connected to the receptors, which have been linked to prostate cancer and gut serotonin production.

Manglik envisions a future where novel smells can be designed based on an understanding of how a chemical’s shape leads to a perceptual experience, not unlike how pharmaceutical chemists today design drugs based on the atomic shapes of disease-causing proteins.

Journal Reference:

  1. Billesbølle, C.B., de March, C.A., van der Velden, W.J.C. et al. Structural basis of odorant recognition by a human odorant receptor. Nature (2023). DOI: 10.1038/s41586-023-05798-y
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