Artificial Receptors Could Help Us Solve the Puzzle of Olfaction

Scent molecules “jiggle” inside of model olfactory receptors to activate them, revealing some of the molecular motions that create our sense of smell.

Our noses can effortlessly distinguish the aroma of coffee from the tang of gasoline, yet how they do it has long been a mystery.

In a study that appears Oct. 30 in Nature, scientists at Duke University School of Medicine, UC San Francisco and City of Hope provide a glimpse into the complex mechanics that enable the nose to decode an astonishing range of odors with precision.

The team designed four model receptors based on the shapes of the 400 odorant receptors (ORs), then took snapshots at atomic-level resolution as the receptors encountered scent molecules.

“Every time you smell something like coffee or bread, you’re actually picking up hundreds of different odor molecules,” said co-senior author Hiro Matsunami, PhD, professor of molecular genetics and microbiology at Duke School of Medicine. “Our brain distinguishes various odors seamlessly, but understanding how that works at a molecular level has been a challenge.”

The study focused on two main types of odorant receptors: Class I receptors, which are sensitive to cheese or vinegar-like smells, and Class II receptors, which are more versatile and pick up a wider range of scents.

Real human receptors, however, were “impossible to make in a test tube,” precluding any detailed analysis of how they interacted with scents, explained Aashish Manglik, MD, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy and co-senior author of the paper.

So, the team engineered four model ORs based on the structure of some of the major subtypes of the human OR to see how they worked.

Advanced cryo-electron microscopy (cryo-EM) allowed the team to capture detailed 3D images of the model ORs as they detected scent molecules.

To visualize how these receptors move and change with different odors, City of Hope scientists created computer simulations to model these movements.

“This helps us understand how smell receptors recognize and respond to odors in real life,” said co-senior study author Nagarajan Vaidehi, PhD, professor and chair of the Department of Computational and Quantitative Medicine within Beckman Research Institute of City of Hope.

A loose fit between scent and receptor

Some receptors in the body work with the rigidity and precision of a lock: they are activated only when the corresponding molecular “keys” or engages with them.

But the model ORs behaved differently.

“The way these odor molecules bind these receptors is surprisingly dynamic and flexible – the key jiggles around in the lock quite a bit to open it,” Manglik said.

This flexibility could help explain why individual ORs can sense so many different odorants.

“During evolution, ORs had to diversify to detect ever-wider ranges of odorants,” said co-first author of the paper Claire de March, PhD, professor at the Université Paris-Saclay and former Duke researcher. “These model ORs are just the start for understanding olfaction.”

Additional authors: Ning Ma and Christian B. Billesbolle were also co-first authors of the paper. Other authors include Linus Li; Jeevan Tewari; Claudia Llinas del Torrent; Wijnand J.C. van der Velden; Ichie Ojiro; Ikumii Takayama; and Bryan Faust.

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