Our noses can effortlessly distinguish the aroma of coffee from that of gasoline, but how it does this has long been a mystery.

In a study published on October 30 in Naturescientists from Duke University School of Medicine, UC San Francisco and City of Hope provide insight into the complex mechanisms that allow the nose to accurately decode an astonishing range of odors.

The team designed four receptor models based on the shapes of the 400 odorant receptors (ORs), then took snapshots at atomic resolution when the receptors encountered odorant molecules.

“Every time you smell something like coffee or bread, you pick up hundreds of different odor molecules,” said Hiro Matsunami, PhD, professor of molecular genetics and microbiology at the Duke School of Medicine. “Our brains easily distinguish various odors, but understanding how this works at the molecular level has been a challenge.”

The study focused on two main types of odorant receptors: class I receptors, which are sensitive to the odors of cheese or vinegar, and class II receptors, which are more versatile and pick up a wider range of perfumes.

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

So the team designed four operating room models based on the structure of some of the main subtypes of the human operating room to see how they worked.

Advanced cryo-electron microscopy (cryo-EM) allowed the team to capture detailed 3D images of model operating rooms as they detected odorous 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 olfactory receptors recognize and respond to odors in real life,” said Nagarajan Vaidehi, PhD, professor and chair of the Department of Computational and Quantitative Medicine at City of Hope’s Beckman Research Institute.

A loose fit between scent and receiver

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

But the model operating rooms behaved differently.

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

This flexibility could help explain why individual operating rooms can detect so many different odors.

“Over the course of evolution, operating rooms have had to diversify to detect ever-wider ranges of odorants,” said paper co-author Claire de March, PhD, a professor at the University Paris-Saclay and former Duke researcher. “These OR models are just the beginning of 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 JC van der Velden; Ichie Ojiro; Ikumii Takayama; and Bryan Faust.