More than one kind of molecule evokes the smell of grapefruit. Even molecules with very different frameworks can strongly activate the same odorant receptor. A 2025 study identified OR2M2 as one such shared detector.
The discovery depended on a technique that makes nasal receptors easier to study in cultured cells. The researchers modified the ends of the receptor proteins, allowing them to measure responses from receptors that had been unresponsive in earlier experimental systems. Applying the method broadly, they investigated receptor–molecule relationships for characteristic odors of fruit, flowers, wood, cork-tainted wine, and more.
First, making nasal receptors work in cells
Odorant receptors are proteins that detect odor molecules and transmit signals into cells. Yet when human receptors are produced in laboratory cells, they may not reach the cell surface in sufficient quantities or generate the expected response. If adding a molecule produces no visible response, it can be difficult to tell whether the molecule is a poor match for the receptor or the receptor is not working properly in the experimental system.
The team therefore used the sequence of a relatively well-functioning receptor as a guide to progressively modify the protein’s C terminus. This approach adjusts the intracellular end while retaining the central region that receives odor molecules. They sought suitable sequences separately for two receptor classes with different properties.
The experiments used human-derived HEK293T cells and proteins that support receptor function. Intracellular signaling after receptor activation was measured as luminescence, while the amount of receptor at the cell surface was measured separately by flow cytometry. The design aimed not only to enhance responses but also to examine why they had become easier to measure.
Greater assay sensitivity reveals previously unseen responses
For OR7C1, for example, the optimized terminus reduced the odorant concentration needed to reach a reference response to approximately one 105th of that required by the conventional form. Several other receptors also improved, and clear responses appeared in receptors such as OR2M2 and OR7A10 whose responses could not be detected with the conventional forms.
This means that the cultured-cell assay became more sensitive. It does not mean that people became 105 times more sensitive to the odor. Improved responses also did not invariably coincide with increased receptor abundance at the cell surface, leaving questions about how terminal modifications affect signaling and other processes.
Using this approach, the researchers prepared 486 constructs, including genetic variants, derived from 391 receptor genes. They screened responses to characteristic odorants and then confirmed them in concentration–response tests. Further testing with 438 fragrance ingredients, supplemented where necessary by acids, sulfur compounds, and structurally related molecules, characterized the response profiles. Structure–response comparisons involved at least two independent experiments, with at least two replicates in each.
Different molecules share a grapefruit character
OR2M2 responded to nootkatone, a characteristic grapefruit odorant, and to the sulfur-containing grapefruit mercaptan. These two compounds have very different chemical structures. Responses were also observed to structurally distinct synthetic fragrance ingredients described as grapefruit-like.
By contrast, the closely related receptor OR2M3 responds to onion-like sulfur compounds. In these comparisons, OR2M3 did not show significant responses to the grapefruit-type molecules, and OR2M2 did not respond to the onion-like analogs tested. A shared sulfur atom or a similar receptor sequence alone therefore cannot fully explain odor character.
Other examples also connected similarly smelling compounds with a shared receptor. Rose-like citronellol and geraniol, as well as structurally different synthetic rose odorants, activated OR2A25. The study linked vanilla-like molecules with OR10G3, patchoulol, a characteristic patchouli odorant, with OR14J1, and peppery rotundone with OR7A10.
The study was not limited to pleasant smells. OR5V1 responded with high sensitivity to 2,4,6-trichloroanisole, a cause of cork taint in wine. Another achievement was to use familiar signature odors as a starting point for identifying functions of receptors whose activating molecules had previously been unknown.
Ambrox offers clues from three-dimensional structure
Another detailed case study concerned ambrox, a characteristic odorant of ambergris that is also used in perfumery. Stereoisomers have the same types of atoms connected in the same way but arranged differently in space; they can differ in detectability and odor character.
The researchers compared 13 odorous stereoisomers. OR7E24, particularly the genetic variant examined, responded strongly to naturally configured ambrox and sharply distinguished different spatial arrangements. OR7A17, which is associated with woody odors, also responded to ambrox, but its responses differed less sharply among the isomers than those of OR7E24.
Importantly, the explanation did not stop at a single receptor. Some isomers detectable by humans at low amounts acted weakly on OR7E24 but strongly on OR7A17. Adjusting the experimental sensitivities of the two receptors for comparison improved the correspondence between amounts needed to activate cells and amounts detectable by people. This provides a concrete example of considering the relationship between stereochemistry and odor quality through more than one detector.
How does one receptor relate to a whole odor?
The authors interpret their findings as showing that a small number of highly sensitive receptors can play important roles in supporting particular odor qualities for molecules with distinct odor characters. This gives greater weight to individual receptor selectivity than explanations emphasizing combinations of many receptor responses.
However, the authors retain a role for combinations. Nootkatone, for example, has both grapefruit-like and woody aspects, while ambrox has ambergris-like and woody aspects. Responses at different receptors may contribute to these qualities, and perfumes and foods contain mixtures of many molecules. Identifying a detector for one characteristic aspect is not the same as assigning an entire odor to one receptor.
Not every receptor worked adequately in the present assays. The researchers did not identify the expected specific receptors for eucalyptol or sandalwood-like odors. Further work is also needed to bridge experiments on modified receptors in cultured cells with the operation of the actual nose and brain.
The human detection-threshold and odor-description data drew on approximately 40 years of measurements by trained employees aged 18–65. The ambrox comparisons likewise used previously reported evaluations. This was not a study newly testing every odor in one uniform, large participant cohort, an important consideration when interpreting the correspondence with cellular responses.
Summary
By adjusting receptor termini to improve the sensitivity of cultured-cell assays, this study identified receptors responding to signature molecules associated with grapefruit, rose, patchouli, cork taint, and other odors. The shared activation of OR2M2 by structurally different grapefruit odorants provides a clear example of similarly smelling molecules having a common detector.
For ambrox, combining differences in stereochemistry with the responses of two receptors helped reveal a correspondence with human detectability. Although odors as a whole are complex, the detectors supporting their characteristic aspects can be examined one by one. Improvements in measurement have widened the path connecting the language of smell with molecular function.
Funding and competing interests: The research was funded entirely by Givaudan Schweiz AG. All five authors were employees of the company at the time and declared that they received no compensation beyond their salaries. A patent application for commercial use of the modified receptors, WO2024126820, was also disclosed.
Reference
Emter R, Merillat C, Buchli F, Flachsmann F, Natsch A. Decoding human olfaction by high heterologous expression of odorant receptors detecting signature odorants. Current Biology. 2025;35(21):5252–5263.e4. doi:10.1016/j.cub.2025.09.041
