In this illustration, the propionic acid odorant—one of the compounds that give Swiss cheese its distinct smell—activates the odorant receptor protein, OR51E2. Researchers recently discovered how odor receptors are activated in humans and other vertebrate species. Illustration created by Claire de March.

Take a whiff of a hyacinth flower and, in a matter of seconds, the olfactory receptor neurons in your nose pick up the smell; the receptors in those neurons bind to the odor molecules, triggering a nerve impulse that travels along the olfactory nerve to the brain. The olfactory nerve then sends the nerve impulse to the olfactory bulb—a small structure at the base of the brain—which processes the information and sends it to other parts of the brain. For the first time, researchers have an answer to how these odor receptors are activated in humans and other vertebrate species. As part of this effort, they looked at how odor receptors, which belong to G protein-couple receptors or GPCRs—bind to the odor molecule. They recently published their findings in Nature. For starters, humans have about 400 receptors, and each receptors is tuned to a specific set of smells. That means that every smell we take in—from freshly cut grass to aged cheese—activates a specific combination of receptors as each odor molecule binds to multiple odor receptor proteins. In order to study this, however, researchers would first need to study the structure of the odor receptor protein to understand how and why they bind to specific molecules. For that, they rely on the cryo-electron microscopy or cryo-EM technique that allows them to study the 3D structure of proteins and molecules. But there have been two challenges related to this: 1. Most receptor proteins are difficult to produce outside the nose; 2. Researchers have typically needed milligrams of purified protein to accurately determine their structure. Over the last few years, however, the cryo-EM technique has advanced to a point where researchers need a lot less of the receptor protein—micrograms instead of milligrams—to determine its structure. In addition, as part of this recent effort, out of the 400 or so receptors, researchers identified a single receptor—OR51E2—that’s most efficient in producing proteins, as it turns out not just in the nose but also in the kidney cells. This particular receptor responds to the acids propionate and acetate—produced by our gut bacteria and abundant in our bodies, particularly in our gut cells. “If you think about olfactory receptors, they're obviously expressed in the olfactory sensor neurons and detect odorants, but then some of the receptors are actually expressed in other cells, like gut cells, or kidney cells, or some other places, to sense things in the body,” says Hiroaki Matsunami, author on the study and Professor of Molecular Genetics and Microbiology and of Neurobiology at Duke University’s School of Medicine. He’s also part of the NeuroNex project, Odor2Action: Discovering Principles of Olfactory-Guided Natural Behavior, which is focused on understanding how we detect natural chemical odorants. “That, by itself, is interesting,” says Matsunami. “For us, it indicates that this particular receptor is different because it's not only functioning in the nose, but also functioning in other cells. We thought it has a better chance to be expressed.” Next, researchers looked at why OR51E2 responded to those particular short-chain fatty acids and not, for instance, longer-chain carboxylic acids. They tested this by stimulating OR51E2-expressing cells with a set of carboxylic acids and monitoring the activation of OR51E2. Understanding the structural analysis of the protein was key because it not only helps shed light on how different receptors are tuned but also allows researchers to make mutations to engineer the receptor structure to change its tuning. “We definitely need to experimentally determine more structures, but we are now capable of predicting or modeling the structure of all the receptors,” says Matsunami. Once we have it, it’s possible to computationally screen what kinds of odorants may bind to a particular odorant receptor.” This would help researchers efficiently screen newer chemicals that may be used in perfumes, flavors, or food additives, for instance.