Painting a picture that makes sense and scents

The sensation of smell, olfaction, has an important role in to play in the palatability and flavour of food. To gain a better understanding of olfaction, scientists at UC San Francisco (UCSF) have created a molecular-level, 3D picture of how an odour molecule activates a human odorant receptor, a crucial step in deciphering the sense of smell.

The findings, published in Nature, are set to reignite interest in the science of smell with implications for fragrances, food science and beyond. Olfactory (or odorant) receptors — proteins that bind odour molecules on the surface of olfactory cells — make up half of the largest, most diverse family of receptors in our bodies.

According to Aashish Manglik, MD, PhD, an associate professor of pharmaceutical chemistry and a senior author of the study, the goal is to map the interactions of thousands of scent molecules with hundreds of olfactory 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 odour molecules react with their corresponding odour receptors,” Manglik said.

Painting a picture of the scent 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 odour 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, PhD, 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 visualise 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, PhD, 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 for a long time,” Billesbøelle said. “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.”

This molecular snapshot showed that propionate sticks tightly to OR51E2 thanks to a very specific fit between odorant and receptor. The finding jibes with one of the duties of the olfactory system as a sentinel for danger.

While propionate contributes to the rich, nutty aroma of Swiss cheese, on its own, its scent is much less appetising.

“This receptor is laser focused on trying to sense propionate and may have evolved to help detect when food has gone bad,” Manglik said. Receptors for pleasing smells like menthol or caraway might instead interact more loosely with odorants, he speculated.

Just a whiff

Along with employing a large number of receptors at a time, another interesting quality of the sense of smell is our ability to detect tiny amounts of odours that can come and go. To investigate how propionate activates this receptor, the collaboration enlisted quantitative biologist Nagarajan Vaidehi, PhD, at City of Hope, who used physics-based methods to simulate and make movies of how OR51E2 is turned on by propionate.

“We performed computer simulations to understand how propionate causes a shape change in the receptor at an atomic level,” Vaidehi said. “These shape changes play a critical role in how the odorant receptor initiates the cell signalling process leading to our sense of smell.”

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.

“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.”

Image credit: iStock.com/Angelafoto