The Third Extracellular Loop of Mammalian Odorant Receptors Is Involved in Ligand Binding

Shim, Tammy; Pacalon, Jody; Kim, Won-Cheol; Cong, Xiaojing; Topin, Jérémie; Golebiowski, Jérôme; Jung, Da Hae

doi:10.3390/ijms232012501

Cited by 7 publications

(4 citation statements)

References 44 publications

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“…Olfactory receptors display significant sequence variation in extracellular loop 3 (ECL3), a region previously shown to be critical for recognition of highly diverse odorants 36,37 . We therefore aimed to understand the involvement of ECL3 in propionate binding to OR51E2, and more generally, how ECL3 may drive the conformational changes in TM6 necessary for OR activation ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of odorant recognition by a human odorant receptor

Billesboelle

March

Velden

et al. 2022

Preprint

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Our sense of smell enables us to navigate a vast space of chemically diverse odor molecules. This task is accomplished by the combinatorial activation of approximately 400 olfactory G protein-coupled receptors (GPCRs) encoded in the human genome. How odorants are recognized by olfactory receptors (ORs) remains mysterious. Here we provide mechanistic insight into how an odorant binds a human olfactory receptor. Using cryogenic electron microscopy (cryo-EM), we determined the structure of active human OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an olfactory receptor. Molecular dynamics simulations demonstrate propionate-induced conformational changes in extracellular loop 3 to activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate OR, providing insight into how this large family of GPCRs enables our olfactory sense.

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Section: Introductionmentioning

confidence: 99%

Structural basis of odorant recognition by a human odorant receptor

Billesboelle

March

Velden

et al. 2022

Preprint

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“…(iii) Similarly, the extracellular loops of these LSEs display high sequence heterogeneity, typically containing charged and polar residues. In terms of length, the patterns mirror those seen in vertebrate olfactory receptors: ECL2 is notably longer, spanning 25 to 30 residues (85), whereas ECL1 and ECL3 range from 15 to 20 residues across various groups (86,87).…”

Section: Signatures and The Rate Of Evolution Of The Ligand-binding R...mentioning

confidence: 60%

Evolutionary Dynamics of Lineage-Specific Class-A GPCR Subsets Reveal Widespread Chemosensory Roles and Adaptations in Lophotrochozoa

Nath,

Panda,

Siuli

et al. 2024

Preprint

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Detecting external chemosensory cues via Class-A G protein-coupled receptors (GPCRs) is essential for behavioral and biological functions, influencing animal evolution and ecological adaptations. While well-studied in vertebrates and echinoderms, their role in major clades like Lophotrochozoa is less understood despite their remarkable ecological adaptations. Utilizing 238 lophotrochozoan genomes across eight phyla, we conducted a large-scale comparative genomics analysis to identify lineage-specifically expanded subsets (LSEs) of Class-A GPCRs adapted for chemoreception. Using phylogeny and orthology-based clustering, we differentiated these expansions from conserved orthogroups of endogenous ligand-binding GPCRs. LSEs correlated with adaptations to diverse habitats, with whole-genome duplications having limited impact. Across phyla, species in coastal, freshwater, and terrestrial habitats exhibited large and diverse LSEs, while those adapted to extreme deep-sea environments, parasitic lifestyles, or alternative chemosensory mechanisms showed consistent reductions. Sequence heterogeneity, positive selection, and ligand-binding pocket flexibility in these LSEs further underscored adaptations to environmental signals. These findings provide foundational insights into Class-A GPCR-mediated chemoreception across Lophotrochozoa.TeaserUnveiling correlations between lophotrochozoans habitat adaptations and lineage-specific changes in Class-A GPCR repertoire.

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“…Despite their potential as drug targets, the study of ORs has been hindered by the lack of structural data: the first experimental structure was published in March 2023, consisting of human OR51E2 in its active state, bound to an agonist (propionate) and a mini-G protein. In light of this limitation, the modeling community has approached the OR family with different techniques, from homology modeling − to de novo structure prediction. , Such computational models have provided useful insights into the mechanism of OR-ligand recognition at the atomistic level as well as pinpointed crucial residues for OR function, in combination with experimental mutagenesis data.…”

mentioning

confidence: 99%

Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor

Pirona,

Ballabio,

Alfonso-Prieto

et al. 2024

J. Chem. Inf. Model.

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Conformational changes as well as molecular determinants related to the activation and inactivation of olfactory receptors are still poorly understood due to the intrinsic difficulties in the structural determination of this GPCR family. Here, we perform, for the first time, the in silico inactivation of human olfactory receptor OR51E2, highlighting the possible role of calcium in this receptor state transition. Using molecular dynamics simulations, we show that a divalent ion in the ion binding site, coordinated by two acidic residues at positions 2.50 and 3.39 conserved across most ORs, stabilizes the receptor in its inactive state. In contrast, protonation of the same two acidic residues is not sufficient to drive inactivation within the microsecond timescale of our simulations. Our findings suggest a novel molecular mechanism for OR inactivation, potentially guiding experimental validation and offering insights into the possible broader role of divalent ions in GPCR signaling.

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The Third Extracellular Loop of Mammalian Odorant Receptors Is Involved in Ligand Binding

Cited by 7 publications

References 44 publications

Structural basis of odorant recognition by a human odorant receptor

Structural basis of odorant recognition by a human odorant receptor

Evolutionary Dynamics of Lineage-Specific Class-A GPCR Subsets Reveal Widespread Chemosensory Roles and Adaptations in Lophotrochozoa

Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor

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