Human olfactory receptors belong to a huge family of proteins known as G protein-coupled receptors (GPCRs). Located inside cell membranes, these proteins contribute to a wide range of physiological processes by detecting all kinds of stimuli, from light to hormones.
Over the past two decades, researchers have determined the detailed structure for the growing number of GPCRs—but not for the olfactory receptors among them. To get enough receptors for these studies, the researchers had to produce them in cultured cells. However, olfactory receptors often refuse to mature properly when growing outside of olfactory neurons, their natural habitat.
To overcome this problem, Matsunami and Claire Marchwho had been a research associate in Matsunami’s lab, began to explore the possibilities of genetically modified olfactory receptors to make them more stable and easier to grow in other cells. They join forces with Aashish Manglika biochemist at the University of California, San Francisco, and Christian Billesbellea senior scientist in Manglik’s lab.
Although this effort is progressing, the team decided to take one more step toward extracting the natural receptor. Manglik recalls thinking: “It will probably fail just like everyone else has. “[But] we should try it anyway.
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. Thanks to Billesbølle’s meticulous efforts, they obtained enough OR51E2 for study. They then exposed the receptor to an odor molecule they knew it had detected: propionate, a short fatty acid produced by fermentation.
To produce detailed images of the receptor and propionate locked together, the interaction that activates sensory neurons, they used cold electron microscopy, an advanced imaging technique. helps to record snapshots of proteins that have been frozen rapidly.
The team found that in the structure of the interlocking molecules, OR51E2 traps propionate in a small pocket. As they expand the vesicle, the receptor loses most of its sensitivity to propionate, and another small molecule normally activates it. The fine-tuned receptor favors larger odor molecules, which confirms that the size and chemistry of the binding pocket regulates the receptor to detect only a narrow subset of molecules.
Structural analysis also discovered a small, flexible loop on the top of the receiver, which locks down like a flap on a bag when an odor molecule binds within it. According to Manglik, this finding suggests that this highly variable ring fragment may contribute to our ability to detect diverse chemistries.
Basic logic of scent
And the OR51E2 may still have other secrets to share. Although the study focused on propionate vesicles, the receptor may possess other binding sites for other odors or for the chemical signals it may encounter, the researchers say. right in the tissues outside the nose.
In addition, the microscopy images reveal only a static structure, but these receptors are in fact dynamic. Nagarajan Vaidehi, a computer chemist at the City of Hope’s Beckman Institute, who was also involved in the study. Her team used computer simulations to visualize how the OR51E2 might move when it’s not frozen.
