When an odor molecule is bound to an olfactory receptor, the channel pore (blue), dilates (pink). Credit: Laboratory of Neurophysiology and Behavior, The Rockefeller University.All senses have to deal with the richness and variety of the world. However, nothing compares to the challenges faced by our sense of smell. To sense the rainbow's colors, we only need three eyes. This is because the different hues are merely light-waves. They vary in frequency across one dimension. However, the vibrant colors of the world are nothing compared to the complex chemical world with its millions of odors. Each molecule is made up of hundreds of molecules and each one has a unique shape, size, and property. For example, the smell of coffee is a mixture of over 200 chemical components. Each one of these molecules has a unique structure and each one doesn't smell like coffee.Vanessa Ruta, Rockefeller neuroscientist, says that the olfactory system must recognize large numbers of molecules using only a handful of odor receptors. It is clear that the olfactory system had to develop a different type of logic than other sensory systems.Ruta and her collaborators have provided the first molecular images of an olfactory receptor working in a study. This provides answers to the long-standing question of smell recognition.Nature published the findings. They show that olfactory and other receptors follow a unique logic. Although most receptors can only pair with a handful of molecules in a locked-and-key fashion (which is the case for most), most olfactory molecules can bind to many molecules. Each receptor can respond to many chemical components because of their promiscuity in pairing. The brain then can determine the odor by looking at the activation patterns of different combinations of receptors.Holistic recognitionThirty-years ago, olfactory receptors was discovered. Scientists haven't been able to see these receptors up close or decode their mechanistic and structural workings. This is partly because they didn't lend themselves well to molecular imaging techniques. The complexity of the matter is complicated by the fact that each receptor can respond to different compounds, both chemically and structurally.Josefina Del Mrmol, a Ruta postdoc, says, "To understand odorant recognition, we must know how one receptor can recognize multiple chemicals. This is a key feature in how the olfactory systems works and has been a mystery."Ruta and del Mrmol along with Mackenzie Yedlin (a research assistant in our lab), set out to solve the structure of an odor receptor using recent advances in cryoelectron microscopy. This technique involves beaming electrons at frozen specimens to reveal very small molecular structures in 3D down to their individual elements.The jumping bristletail was chosen as the next experiment. It is a ground-dwelling insect with a genome that has been sequenced recently and only five types of olfactory receptors. The jumping bristletail has a simple olfactory system, but its receptors are part of a large group of receptors that could be found in hundreds of thousands of insect species. These receptors, despite their variety, function in the same way. They create an ion channela pores through which charged particles flow. This opens only when the receptor meets its target odorant. It then activates the sensory cells that trigger the sense of smell.OR5, a jumping bristletail receptor with wide recognition ability that responds to 60% of the small molecules tested by the researchers, was chosen.The researchers then examined OR5's single structure and bound it to a chemical. Eugenol is a common odor molecule. DEET repels insects. Ruta states that comparing the three structures revealed a lot. "One of the most beautiful things that you can see is the fact that the pore in the unbound structure is closed. However, in the structure where it is bound with either DEET or eugenol, the pore has dilapidated, which allows ions to flow.The team was able to examine the structures and determine how the different chemically distinct molecules would bind to the receptor. Two theories have been proposed about the interactions of odor receptors with molecules. The first is that receptors evolved to recognize large areas of molecules by responding only to certain features of the molecule. Others have suggested that each receptor has multiple pockets, which allows it to hold a variety of molecules.Ruta's findings were not compatible with either of these scenarios. Both DEET and Eugenol both bind in the same place and fit perfectly within a small pocket of the receptor. Surprisingly, the weak chemical bonds formed by the amino acids in the pocket with the odorants were not strong and selective. While in many other systems receptors and target molecules are chemical matches, they were more friendly here. Ruta states that these non-specific chemical interactions enable different odorants be recognized. This is because the receptor does not discriminate between a particular chemical feature. Ruta says that the receptor is recognizing the general chemical nature of an odorant.As computational modeling showed, many other odor molecules could be accommodated in the same pocket.Ruta clarifies that the receptor's promiscuity does not mean it lacks specificity. Each receptor is sensitive to many molecules but responds differently to different molecules. A simple mutation in one of the binding sites' amino acids would change the receptor's preference to bind with other molecules. This finding helps explain how insects are able to create a wide variety of odor receptor types that suit their varied lifestyles and habitats.Ruta believes that these findings could be representative of many olfactory sensory receptors. Ruta says that the findings are indicative of key principles in odorant detection, not just in insects' receptors, but also in our own receptors. These receptors must detect and discriminate rich chemicals.More information: Nature, The structural basis for insect olfactory receptors' odor recognition. (2021). www.nature.com/articles/s41586-021-03794-8 Journal information: Nature The structural basis of odorant recognition in insect olfactory receptors,(2021). DOI: 10.1038/s41586-021-03794-8
