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Scientists created first molecular level 3D picture of how an odor molecule activates a human odor receptor

Scientists have created the first molecular-level 3D picture of how an odor molecule activates a human odor receptor, a crucial step in deciphering the sense of smell. Scientists are helping to break a long-standing impasse in our understanding of smell, and the 3D image created has implications for fragrance, food science and more.

A model created by scientists at the University of California San Francisco (UCSF), USA, is poised to reignite interest in the science of smell. The findings were published in the journal Nature.

Odor receptors, the proteins that bind odor molecules on the surface of olfactory cells, make up half of the largest and most diverse family of receptors in our body. Their deeper understanding opens the way to new perspectives on a number of biological processes.

The sense of smell includes about 400 unique receptors

Each of the hundreds of thousands of scents we can detect is made of a mixture of different odor molecules. Each type of molecule can be detected by a number of receptors, creating a puzzle for the brain to solve every time the nose catches a whiff of something new.

“It’s like pressing the keys on a piano to make a chord,” said Hiroaki Matsunami, a professor at Duke University and a close collaborator of Aashish Manglik, associate professor, UCSF.

Matsunami’s work over the past two decades has focused on decoding the sense of smell. “Seeing how the odorant receptor binds the odorant explains how it works at a fundamental level,” Matsunami said. We weren’t able to map smell because without a picture, Manglik said, we didn’t know how the odor molecules would interact with their corresponding odor receptors.

To create the 3D image, the study said, Manglik’s lab used a type of imaging called cryo-electron microscopy (cryo-EM), which allows researchers to see the atomic structure and study the molecular shapes of proteins.

But before Manglik’s team could visualize the odorant receptor binding to the odorant, they first had to purify enough of the receptor protein. Odor receptors are notoriously difficult, some say impossible to make in the lab for such purposes.

The Manglik and Matsunami teams looked for an odor receptor that was abundant in the body and nose, and thought it might be easier to make artificially and, according to the study, could also detect water-soluble odorants.

They settled on a receptor called OR51E2, which is known to respond to propionate – the molecule that contributes to the pungent smell of Swiss cheese.

But even OR51E2 has proven difficult to make in the lab, the study said. Typical cryo-EM experiments require a milligram of protein to produce atomic-level images. However, co-first author Christian Billesbolle, a senior scientist in the Manglik Lab, developed approaches to use just 1/100th of a milligram of OR51E2, bringing a snapshot of the receptor and odorant within reach, the study said.

“We achieved this by overcoming several technical impasses that had suffocated the field for a long time,” said Billesbolle. “This allowed us to capture the first glimpse of an odor binding to a human odor receptor at the very moment the odor is detected,” said Billesbolle.

The study reported that this molecular imaging showed that propionate adheres tightly to OR51E2 due to a very specific connection between the odorant and the receptor. The finding contradicts one of the olfactory system’s duties as a danger watchdog, the study said. While propionate contributes to the rich nutty aroma of Swiss cheese, its aroma on its own is much less appealing.

“This receptor is laser-targeted to try to sense propionate and may have evolved to help detect when food has gone bad,” Manglik said. He speculated that receptors for pleasant odors such as menthol or cumin may instead interact more freely with odorants.

Another interesting property of smell is our ability to detect minute amounts of odors that may come and go.

To find out how propionate activates this receptor, the collaboration enlisted quantitative biologist Nagarajan Vaidehi of City of Hope, USA, who used physical methods to simulate and make movies of how propionate turns on OR51E2.

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

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