Human olfactory receptors belong to a large family of proteins known as G-protein-coupled receptors (GPCRs). Located inside cell membranes, these proteins contribute to many physiological processes by detecting all kinds of stimuli, from light to hormones.
Over the past two decades, researchers have determined detailed structures for an ever-expanding number of GPCRs—but not for the olfactory receptors among them. In order to obtain enough receptors for these studies, researchers must produce them in cultured cells. However, olfactory receptors generally refuse to mature properly when grown outside of olfactory neurons, their natural habitat.
To overcome this problem, Matsunami and Claire de March, who is a research partner in Matsunami’s lab, began to explore the possibility of genetically altering olfactory receptors to make them stronger and easier to grow in other cells. They joined forces with Aashish Manglik, a biochemist at the University of California, San Francisco, and Christian Billesbølle, a senior scientist in Manglik’s lab.
Although this effort was progressing, the team decided to give obtaining a natural receptor another shot. “Maybe it will fail like the others,” Manglik remembers thinking. “[But] we still have to try it.”
They improved their odds by selecting an odor receptor, OR51E2, which is also found outside the nose—in the intestines, kidneys, prostate, and other organs. Through Billesbølle’s painstaking efforts, they obtained enough OR51E2 to study. Then they exposed the receptor to an odor molecule they knew it had detected: propionate, a short fatty acid produced by fermentation.
To create detailed images of the receptor and propionate locked in, the interaction that causes a sensory neuron to fire, they used cryo-electron microscopy, an advanced imaging technique that takes snapshots of fast-freezing protein.
The team found that within the structure of the interlocked molecules, OR51E2 is trapped with propionate inside a small pocket. When they enlarged the pocket, the receptor lost most of its sensitivity to propionate and another small molecule that normally activates it. The tweaked receptor preferred larger odor molecules, proving that the size and chemistry of the binding pocket tuned the receptor to detect only a narrow set of molecules.
The structural analysis also discovered a small, flexible loop on the surface of the receptor, which locks like a pocket lid once the odor molecule binds inside it. The discovery suggests that this highly variable looping piece may contribute to our ability to recognize different chemistry, according to Manglik.
The Underlying Logic of Smell
And OR51E2 may have other secrets to share. Although the study focused on the pocket containing propionate, the receptor may have other binding sites for other odors, or for chemical signals that may be encountered in tissues outside the nose, the researchers said.
Also, the microscopy images only reveal a static structure, but these receptors are actually dynamic, said Nagarajan Vaidehi, a computational chemist at the Beckman Research Institute in the City of Hope who also worked on the study. His team used computer simulations to imagine how OR51E2 would behave if it were not frozen.
