[Reading Science] "Distinguishing 1 Trillion Odors"... The Secret of Human Olfaction

US University of California Research Team Publishes Paper in Nature
First Success in Creating 3D Structure of Specific Olfactory Receptor
Mechanism of Interaction with Odorant Molecules Also Confirmed
A Step Forward in Understanding the Most Complex Sense of Smell

Humans can smell thanks to olfactory receptors located inside the nose. However, little is known about how these receptors detect molecules, perceive them as 'smells,' and accurately distinguish between them. Recently, scientists succeeded in precisely mapping the 3D structure of human olfactory receptors and confirming how they function. This is considered a significant step forward in understanding the most complex of human senses, olfaction.

The international scientific journal Nature published a paper on the 15th (local time) by a research team from the University of California, USA, detailing this achievement. The study meticulously described the 3D structure of an olfactory receptor called 'OR51E2' and demonstrated how it interacts with odor molecules during the process of detecting the smell of cheese.

It was only about 30 years ago that the mechanism by which humans perceive smells was uncovered. In 1991, Richard Axel and Linda Buck discovered olfactory receptors in the noses of mice, for which they were awarded the Nobel Prize in Physiology or Medicine in 2004. The human genome codes for 400 olfactory receptors. Among these, 50 receptors can be linked to specific odors, but the corresponding odors for the remaining 350 receptors remain unknown. In 2014, a study suggested that humans can detect approximately one trillion different odors.

Reference photo.

A single receptor does not correspond to just one odor; rather, several receptors can simultaneously respond to a single substance, and the brain perceives different smells based on this combination. For example, although two floral scents may be similar, the scent of a lily stimulates receptors A, B, and C, while the scent of a magnolia stimulates receptors B, C, and D, allowing subtle differences to be detected. The research team explained, "It is like playing chords on a piano. Just as multiple keys are struck to produce a single note, the human recognition of a specific smell results from the combination of interactions between odor molecules and olfactory receptors."

However, until now, it has been technically challenging to reveal how olfactory receptors recognize specific odor molecules and send signals to the brain. Studying olfactory receptor proteins extracted from animals in the laboratory is extremely difficult. To overcome this, the research team focused solely on one olfactory receptor called 'OR51E2.' This receptor interacts with two molecules: acetate, which causes the smell of vinegar, and propionate, which causes the smell of cheese. It is also found not only in olfactory sensory neurons but also in tissues such as the intestines, kidneys, and prostate, suggesting it may have other functions.

The team isolated OR51E2 and used cryo-electron microscopy, which can capture structures at the atomic level, to analyze the receptor's structure both when bound to propionate and when unbound. They also used computer simulations to analyze how this receptor interacts with odorants at the atomic scale. The results showed that propionate binds to the 'binding pocket' region of the OR51E2 receptor through specific ionic and hydrogen bonds that fix the carboxylic acid group to amino acid arginine residues. In contrast, when arginine in the OR51E2 receptor was mutated, it could no longer bind to propionate. This revealed that the molecular interaction between olfactory receptors and odorants plays a crucial role in the sensory perception of smell.

However, the OR51E2 receptor belongs to a group representing about 10% of human olfactory receptor genes with relatively simple functions. The remaining olfactory receptors are involved in detecting a broader range of odors. Vanessa Ruta, a professor of neuroscience at Rockefeller University, stated, "Olfactory receptors have very diverse mechanisms. Further research and analysis of other receptors will broaden our understanding of the various processes involved in olfactory recognition."