Researchers have recently finally figured out how our noses capture scents. Whether it's the scent of flowers, sweet vanilla, cigarette smoke or the pungent smell of gasoline, it all starts when tiny odor molecules connect to the receptors in our noses. These connections create our likes, dislikes, or tolerances for scents. Scientists have long been eager to understand exactly how our olfactory receptors capture these odor molecules and respond to them in a precise way. But until recently, it was difficult to see how human olfactory receptors worked.
In a new article published in the journal Nature, a team of scientists has finally revealed the hidden 3D shape of an olfactory receptor, while also revealing how a specific substance found in Swiss cheese and body odor is caught. Michael Schmuck, an expert in cheminformatics for odor research at the University of Hertfordshire in the UK, highlights the long-standing mystery that has existed around the actual structure of these odor receptors. Although Schmuck himself was not involved in the study, he considered it a major breakthrough.
Olfactory experts believe they have made progress in understanding how the nose and brain work together to interpret smells, signal spoiled food, trigger childhood memories, help find a partner, and play other important roles. Understanding the process by which complex chemicals are passed from the nose to the brain can be challenging for researchers. Researchers estimate that the human nose contains about 400 olfactory receptors that detect a variety of odor substances called "volatiles," molecules that can easily turn into vapor, from triatomic stinky hydrogen sulfide to musk-like compounds. According to some estimates, there may be about 40 billion or more potential odorants.
Hiroakimatsunami, an olfactory expert at Duke University and a contributor to the latest study, has discovered how we can identify and distinguish a wide range of odor substances. Olfactory receptors are located on the surface of nasal neurons and change shape when they capture odor molecules. This change triggers these neurons to send signals to the areas of the brain responsible for processing odors. Scientists have been hoping to accurately observe the interaction between this receptor and odor molecule to understand its unfolding process in detail.
In 2021, a study revealed the mechanism by which insects smell odors: Scientists at Rockefeller University revealed the olfactory receptor structure of a specific insect and how it recognizes molecules with different chemical compositions. However, this discovery does not provide important insights into human olfaction, as the olfactory receptors of insects are completely different from our olfactory system. Human olfactory receptors are part of a group of proteins called G protein-coupled receptors (GPCRs). These proteins are located within cell membranes and play a role in many biological functions by sensing a variety of stimuli, from light to hormones.
Over the past two decades, scientists have revealed the complex structure of many G protein-coupled receptors (GPCRs), but the structure of olfactory receptors has not yet been discovered. To study these receptors, researchers need to reconstruct them in lab-grown cells. However, when olfactory receptors are cultured in nasal neurons in the laboratory, they often fail to mature properly. To overcome this obstacle, Hiroaki Matsunami and Clairedemarch of the Matsunami laboratory set out to study ways to modify olfactory receptors from a genetic point of view. Their goal is to make these receptors more stable and easier to grow in different types of cells. They collaborated with AashishManglik, a biochemist at the University of California, San Francisco, and Christian Billesb Lle, a senior scientist in Manglik's team.
As the research team continued their work, they decided to try again to extract a natural receptor, although it was expected to fail. Aashishmanglik recalls that they realized that this approach could fail, but they decided it was still worth trying. To increase their chances of success, they opted for an odor receptor, OR51E2, which is found not only in the nose but also in several organs such as the intestines, kidneys, and prostate. Christianbillesb LLE's full dedication paid off, allowing them to obtain enough OR51E2 to use for their research. They then exposed the receptor to a known odor molecule: propionate, a short-chain fatty acid produced by fermentation.
To get a detailed picture of the propionate receptor, the researchers employed cryo-electron microscopy, an advanced imaging method that allows for rapid photographs of frozen protein samples. Their study found that in the binding conformation of these molecules, OR51E2 enclosed propionic acid in a small pocket. When they enlarge this pocket, the receptors become less sensitive to propionic acid and another small molecule, which normally activates the receptors. By tweaking the structure of the receptor, it is more inclined to bind to larger odor molecules, thus verifying the calibration of the receptor by the size and chemistry of this pocket in order to detect a limited range of molecules.
Through detailed analysis, it was found that there is a small, flexible ring-like structure on the surface of the receptor, like a lid, which seals the bag once the odor molecules are trapped inside. Aashishmanglik believes that this flexible structure may play a role in our ability to detect a wide range of compounds. In addition, there may be more discoveries about the OR51E2. Although this study focused primarily on the pockets containing propionate, the researchers believe that propionate receptors may have additional binding sites that can interact with different odors or chemical signals encountered in tissues other than the nasal cavity.
Nagara Janvaidehi, a computational chemist at the Beckman Institute, emphasizes that although the microscope shows a fixed structure, these receptors are actually in constant motion. Her team used computer simulations to visualize how the OR51E2 might move without freezing. For Claire de March, who now works at the French National Center for Scientific Research, the results of OR51E2 have turned years of theory into reality. After focusing on theoretical models of odor receptors, she says the new findings provide the answers she's been looking for in her career. This is the first time she has concretely addressed all the problems she had previously guessed about.
According to Matsunami's research, other human olfactory receptors similar to OR51E2 may work in a similar way. For researchers, pinpointing the structure of olfactory function is an important step in understanding the fundamentals that govern our sense of smell. However, there is still much to discover. Scientists have only a vague idea of which molecules activate about a quarter of human olfactory receptors. Joel Nett, an olfactory neuroscientist at the Monel Center for Chemical Sense, was not involved in the study, believing that having more structures like OR51E2 could help unravel the biological mysteries of smell. As we gain a deeper understanding of how the brain encodes odors, we hope to build reliable models of which odors bind to specific receptors.
Understanding how receptors choose a particular scent is only part of revealing the mystery of scent. Matt Wachowiak, an olfactory neuroscientist who was not involved in the study, noted that understanding olfactory requires decoding how the brain translates signals from these receptors into perception. In fact, most of the odors we encounter come from a mixture of chemicals. Wachowiak highlights the challenge: we need to quickly identify and distinguish between these patterns, regardless of the circumstances. The real challenge is understanding how our brains accomplish this feat.
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