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Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition
Open accessPreprint — published as 10.1016/j.jbc.2022.102331 · Paper page
Abstract
G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed, emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of Nature’s strategy for odor discrimination. This work demonstrates that the extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid of the orthosteric pocket. ECL2 controls the shape and the volume of the odorant-binding pocket, maintains the pocket hydrophobicity and acts as a gatekeeper of odorant binding. The interplay between the specific orthosteric pocket and the variable, less specific ECL2 controls OR specificity and promiscuity. The 3D models enabled virtual screening of new OR agonists and antagonists, exhibiting 78% hit rate in cell assays. This approach can be generalized to structure-based ligand screening for other GPCRs that lack high-resolution 3D structures.
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Metadata
- Authors
- Yu, Y., Pacalon, J., Ma, Z., Xu, L., Belloir, C., Topin, J., Briand, L., Golebiowski, J., & Cong, X.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Centre National de la Recherche Scientifique (FR)
- Shanghai University (CN)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Corresponding author
- Yu, Yiqun
- Golebiowski, Jérôme
- Cong, Xiaojing
- Venue
- Journal of Biological Chemistry
- Publisher
- openRxiv
- Published
- 2021-10-26
- Volume
- 298
- Issue
- 9
- Pages
- 102331-102331
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC9442423
- OpenAlex
- W4289336060
- Cited by
- 28
- References
- 1
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 5 · 2023: 4 · 2022: 1
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- HAL (submittedVersion)
- Funders
- National Natural Science Foundation of China (2018-2021, 31771155, 32070996)
- Fudan University (SYB202002)
- Science and Technology Commission of Shanghai Municipality (21140900600, 2019-2020)
- Université Côte d’Azur
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- olfactory receptors, second extracellular loop, odorant recognition, receptor specificity, orthosteric pocket, odorant binding, virtual screening, structure-based drug design, G protein-coupled receptors, odor discrimination
- MeSH terms
- Protein Conformation, alpha-Helical, Animals, Humans, Ligands, Odorants, Smell, Mutagenesis, Site-Directed, Receptors, Odorant, Mice, Molecular Dynamics Simulation
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