First 3D model of human odor receptor tells us how we smell

A study published on March 15 has ascertained a long-standing puzzle in understanding olfaction by developing the first molecular level.

A 3D picture of how an odor molecule activates a human odorant receptor is a crucial step in deciphering the sense of smell, thanks to UC San Francisco (UCSF) scientists.

According to UCSF, one-half of the most extensive and diverse family of receptors in our bodies are odorant receptors, which are proteins that bind odor molecules on the surface of olfactory cells. They can be better understood, opening new perspectives on various 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. 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.

They pictured Swiss cheese

One-half of the most extensive and diverse family of receptors in our bodies are odorant receptors, which are proteins that bind odor molecules on the surface of olfactory cells. They can be better understood, opening new perspectives on various biological processes.

“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. “Seeing how an odorant receptor binds an odorant explains how this works at a fundamental level,” Matsunami added.

One-half of the most extensive and diverse family of receptors in our bodies are odorant receptors, which are proteins that bind odor molecules on the surface of olfactory cells. They can be better understood, which opens up new perspectives on various biological processes.

The Manglik and Matsunami teams sought an odorant receptor common in both the body and the nose because they reasoned that it could be simpler to create an artificial version of it and one that could also detect water-soluble odorants. Scientists chose the OR51E2 receptor because it has been shown to react to propionate, a compound involved in Swiss cheese's strong flavor.

“We made this happen by overcoming several technical impasses that have stifled the field for a long time,” said Billesbølle. “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.”

Similar to how pharmaceutical chemists currently develop pharmaceuticals based on the atomic forms of disease-causing proteins, Manglik imagines a time when unique fragrances can be created using knowledge of how a chemical's shape affects a person's perception.

“We’ve dreamed of tackling this problem for years,” he said. “We now have our first toehold, the first glimpse of how the molecules of smell bind to our odorant receptors. For us, this is just the beginning.”

The study was published in Nature.

Study abstract:

Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome. How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense.