Authors: Anju Sharma, Bishal Kumar Saha, Rajnish Kumar...

Olfaction is a multi-stage process that initiates with the odorants entering the nose and terminates with the brain recognizing the odor associated with the odorant. In a very intricate way, the process incorporates various components functioning together and in synchronization. OlfactionBase is a free, open-access web server that aims to bring together knowledge about many aspects of the olfaction mechanism in one place. OlfactionBase contains detailed information of components like odors, odorants, and odorless compounds with physicochemical and ADMET properties, olfactory receptors (ORs), odorant- and pheromone binding proteins, OR-odorant interactions in Human and Mus musculus. The dynamic, user-friendly interface of the resource facilitates exploration of different entities: finding chemical compounds having desired odor, finding odorants associated with OR, associating chemical features with odor and OR, finding sequence information of ORs and related proteins. Finally, the data in OlfactionBase on odors, odorants, olfactory receptors, human and mouse OR-odorant pairs, and other associated proteins could aid in the inference and improved understanding of odor perception, which might provide new insights into the mechanism underlying olfaction. The OlfactionBase is available at https://bioserver.iiita.ac.in/olfactionbase/.

Topics: Animals; Databases, Factual; Humans; Mice; Odorants; Olfactory Receptor Neurons; Receptors, Odorant; Signal Transduction; Smell

PubMed: 34469532
DOI: 10.1093/nar/gkab763

Authors: Tarsila G Castro, Carla Silva, Teresa Matamá...

The binding of known odorant molecules to the human odorant-binding protein (hOBP) was evaluated Docking experiments elucidate the preferable binding site and binding affinity of odorant molecules to hOBP. The physicochemical properties molecular weight (MW), vapor pressure (Vp), hydrophobicity level (logP), number of double bonds (NºDB), degree of unsaturation (DoU) and the chemical classification, were selected for the study of odorant modulation. Here, these properties were analyzed concerning 30 pleasant and 30 unpleasant odorants, chosen to represent a wide variety of compounds and to determine their influence on the binding energy to hOBP. Our findings indicate that MW, logP and Vp are the most important odorant variables, directly correlated to odorant-binding energies (DG) towards hOBP. Understanding how the odorants behave when complexed with the OBP in human olfaction opens new possibilities for the development of future biotechnological applications, including sensory devices, medical diagnosis, among others.

Topics: Binding Sites; Carrier Proteins; Computer Simulation; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Conformation; Molecular Dynamics Simulation; Molecular Weight; Odorants; Principal Component Analysis; Protein Binding; Receptors, Odorant; Thermodynamics

PubMed: 33499295
DOI: 10.3390/biom11020145

Authors: Ho Ka Chan, Fabian Hersperger, Emiliano Marachlian...

In natural environments, odors are typically mixtures of several different chemical compounds. However, the implications of mixtures for odor processing have not been fully investigated. We have extended a standard olfactory receptor model to mixtures and found through its mathematical analysis that odorant-evoked activity patterns are more stable across concentrations and first-spike latencies of receptor neurons are shorter for mixtures than for pure odorants. Shorter first-spike latencies arise from the nonlinear dependence of binding rate on odorant concentration, commonly described by the Hill coefficient, while the more stable activity patterns result from the competition between different ligands for receptor sites. These results are consistent with observations from numerical simulations and physiological recordings in the olfactory system of insects. Our results suggest that mixtures allow faster and more reliable olfactory coding, which could be one of the reasons why animals often use mixtures in chemical signaling.

Topics: Animals; Bees; Complex Mixtures; Insecta; Models, Theoretical; Odorants; Olfactory Bulb; Olfactory Receptor Neurons; Receptors, Odorant; Smell

PubMed: 30532147
DOI: 10.1371/journal.pcbi.1006536

Authors: Majid Saberi, Hamed Seyed-Allaei

Which properties of a molecule define its odor? This is a basic yet unanswered question regarding the olfactory system. The olfactory system of Drosophila has a repertoire of approximately 60 odorant receptors. Molecules bind to odorant receptors with different affinities and activate them with different efficacies, thus providing a combinatorial code that identifies odorants. We hypothesized that the binding affinity of an odorant-receptor pair is affected by their relative sizes. The maximum affinity can be attained when the molecular volume of an odorant matches the volume of the binding pocket. The affinity drops to zero when the sizes are too different, thus obscuring the effects of other molecular properties. We developed a mathematical formulation of this hypothesis and verified it using Drosophila data. We also predicted the volume and structural flexibility of the binding site of each odorant receptor; these features significantly differ between odorant receptors. The differences in the volumes and structural flexibilities of different odorant receptor binding sites may explain the difference in the scents of similar molecules with different sizes.

Topics: Animals; Binding Sites; Drosophila; Drosophila Proteins; Models, Biological; Models, Theoretical; Odorants; Protein Binding; Receptors, Odorant

PubMed: 27112241
DOI: 10.1038/srep25103

Authors: Claire A de March, William B Titlow, Tomoko Sengoku...

The perception of odors relies on combinatorial codes consisting of odorant receptor (OR) response patterns to encode odor identity. Modulation of these patterns by odorant interactions at ORs potentially explains several olfactory phenomena: mixture suppression, unpredictable sensory outcomes, and the perception of odorant mixtures as unique objects. We determined OR response patterns to 4 odorants and 3 binary mixtures in vivo in mice, identifying 30 responsive ORs. These patterns typically had a few strongly responsive ORs and a greater number of weakly responsive ORs. ORs responsive to an odorant were often unrelated sequences distributed across several OR subfamilies. Mixture responses predicted pharmacological interactions between odorants, which were tested in vitro by heterologous expression of ORs in cultured cells, providing independent evidence confirming odorant agonists for 13 ORs and identifying both suppressive and additive effects. This included 11 instances of antagonism of ORs by an odorant, 1 instance of additive responses to a binary mixture, 1 instance of suppression of a strong agonist by a weak agonist, and the discovery of an inverse agonist for an OR. Interactions between odorants at ORs are common even when the odorants are not known to interact perceptually in humans, and in some cases interactions at mouse ORs correlate with the ability of humans to perceive an odorant in a mixture.

Topics: Aldehydes; Animals; Cells, Cultured; Female; Lactones; Male; Mice; Mice, Inbred C57BL; Odorants; Olfactory Receptor Neurons; Pentanols; Receptors, Odorant; Smell

PubMed: 32061665
DOI: 10.1016/j.mcn.2020.103469

Authors: Josefina Del Mármol, Mackenzie A Yedlin, Vanessa Ruta...

Olfactory systems must detect and discriminate amongst an enormous variety of odorants. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists-the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor's tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.

Topics: Animals; Binding Sites; Cell Line; DEET; Eugenol; Insect Proteins; Insecta; Ion Channel Gating; Ion Channels; Models, Molecular; Mutation; Odorants; Protein Binding; Protein Structure, Quaternary; Receptors, Odorant; Substrate Specificity

PubMed: 34349260
DOI: 10.1038/s41586-021-03794-8

Authors: Franziska Haag, Antonella Di Pizio, Dietmar Krautwurst...

Mammals perceive a multitude of odorants by their chemical sense of olfaction, a high-dimensional stimulus-detection system, with hundreds of narrowly or broadly tuned receptors, enabling pattern recognition by the brain. Cognate receptor-agonist information, however, is sparse, and the role of broadly tuned odorant receptors for encoding odor quality remains elusive. Here, we screened IL-6-HaloTag®-OR2W1 and haplotypes against 187 out of 230 defined key food odorants using the GloSensor™ system in HEK-293 cells, yielding 48 new agonists. Altogether, key food odorants represent about two-thirds of now 153 reported agonists of OR2W1, the highest number of agonists known for a mammalian odorant receptor. In summary, we characterized OR2W1 as a human odorant receptor, with a chemically diverse but exclusive receptive range, complementary to chemical subgroups covered by evolutionary younger, highly selective receptors. Our data suggest OR2W1 to be suited for participating in the detection of many foodborne odorants.

Topics: Animals; Food; HEK293 Cells; Humans; Odorants; Receptors, Odorant; Smell

PubMed: 34857413
DOI: 10.1016/j.foodchem.2021.131680

Authors: Rui-Ting Li, Ling-Qiao Huang, Jun-Feng Dong...

Antennae are often considered to be the nostrils of insects. Here, we sequenced the transcriptome of the pheromone gland-ovipositor complex of and discovered that an odorant receptor (OR) gene, , had much higher expression in the ovipositor than in antennae or other tissues. To determine whether the ovipositor was involved in odorant detection, we co-expressed and its co-receptor, , in a oocyte model system, and demonstrated that the OR was responsive to 12 plant odorants, especially Z-3-hexenyl butyrate. These odorants elicited electrophysiological responses of some sensilla in the ovipositor, and and were co-expressed within ovipositor sensilla. Two oviposition preference experiments showed that female moths lacking antennae still preferentially selected oviposition sites containing plant volatiles. We suggest that the expression of in the ovipositor of helps females to determine precise egg-laying sites in host plants.

Topics: Animals; Arthropod Antennae; Female; Gene Expression; Host-Pathogen Interactions; Moths; Odorants; Oils, Volatile; Organ Specificity; Oviposition; Ovum; Pheromones; Plant Oils; Receptors, Odorant; Reproduction; Solanum; Transcriptome; Xenopus

PubMed: 32436842
DOI: 10.7554/eLife.53706

Authors: Claire A de March, Yosuke Fukutani, Aashutosh Vihani...

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. This is why the olfaction community is committed to "de-orphanize" these receptors. Conventional in vitro systems used to identify odorant-OR interactions have utilized incubating cell media with odorant, which is distinct from the natural detection of odors via vapor odorants dissolution into nasal mucosa before interacting with ORs. Here, we describe a new method that allows for real-time monitoring of OR activation via vapor-phase odorants. Our method relies on measuring cAMP release by luminescence using the Glosensor assay. It bridges current gaps between in vivo and in vitro approaches and provides a basis for a biomimetic volatile chemical sensor.

Topics: Cell Line; Cyclic AMP; Humans; Nasal Mucosa; Odorants; Olfactory Perception; Receptors, Odorant; Volatilization

PubMed: 31081824
DOI: 10.3791/59446

Authors: Patrick Pfister, Benjamin C Smith, Barry J Evans...

Most natural odors are complex mixtures of volatile components, competing to bind odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date, surprisingly little is known about how OR antagonism shapes neuronal representations in the detection layer of the olfactory system. Here, we investigated its prevalence, the degree to which it disrupts OR ensemble activity, and its conservation across phylogenetically related ORs. Calcium imaging microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of responses to indole-a commonly occurring volatile associated with both floral and fecal odors-by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we performed single-cell transcriptomics on OSNs exhibiting specific response profiles to a diagnostic panel of odorants and identified three paralogous receptors-Olfr740, Olfr741, and Olfr743-which, when tested in vitro, recapitulated OSN responses. We screened ten ORs from the Olfr740 gene family with ∼800 perfumery-related odorants spanning a range of chemical scaffolds and functional groups. Over half of these compounds (430) antagonized at least one of the ten ORs. OR activity fitted a mathematical model of competitive receptor binding and suggests normalization of OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary, we observed OR antagonism occurred frequently and in a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information appears to occur in the olfactory epithelium prior to transmission of odor information to the olfactory bulb.

Topics: Animals; Gene Expression Profiling; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Odorants; Olfactory Perception; Olfactory Receptor Neurons; Receptors, Odorant; Single-Cell Analysis; Transcriptome

PubMed: 32470365
DOI: 10.1016/j.cub.2020.04.086