Artificial receptors could help us solve the mystery of smell

Our noses can easily distinguish the aroma of coffee from the taste of gasoline, but how they do this has long remained a mystery.

In a study published Oct. 30 in NatureScientists from Duke University School of Medicine, the University of California, San Francisco, and City of Hope provide insight into the complex mechanics that allow the nose to accurately decipher an astonishing range of odors.

The team developed four receptor models based on the shapes of 400 odor receptors (ORs) and then took atomic-scale resolution images as the receptors collided with aroma molecules.

“Every time you smell something like coffee or bread, you’re actually picking up hundreds of different odor molecules,” said co-author Hiro Matsunami, Ph.D., professor of molecular genetics and microbiology at Duke School of Medicine. “Our brains can easily distinguish between different smells, but understanding how it works at the molecular level has been challenging.”

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

However, actual human receptors “cannot be created in vitro,” which precludes any detailed analysis of how they interact with odors, explained Aashish Manglik, Ph.D., professor of pharmaceutical chemistry at the UCSF School of Pharmacy and senior research scientist. . author of the article.

So the team developed four OR models based on the structure of some of the major human OR subtypes to see how they work.

Advanced cryo-electron microscopy (cryo-EM) allowed the team to obtain detailed 3D images of model operating rooms while detecting odor molecules.

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

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

Free correspondence between smell and receptor.

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

But model ORs behaved differently.

“The way odor molecules bind to these receptors is amazingly dynamic and flexible—the key has to wiggle around in the lock for quite a long time to open it,” Manglik said.

This flexibility may help explain why individual operating rooms can smell so many different odors.

“Over the course of evolution, operating systems have had to diversify to detect an increasingly wider range of odorants,” said paper co-author Claire de March, Ph.D., a professor at the University of Paris-Saclay and a former postdoctoral fellow at Duke. “These OR models are just the beginning of our understanding of olfaction.”

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