Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein
Summary: G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224029687 |
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| author | Yanxiao Han John R.D. Dawson Kevin R. DeMarco Kyle C. Rouen Khoa Ngo Slava Bekker Vladimir Yarov-Yarovoy Colleen E. Clancy Yang K. Xiang Surl-Hee Ahn Igor Vorobyov |
| author_facet | Yanxiao Han John R.D. Dawson Kevin R. DeMarco Kyle C. Rouen Khoa Ngo Slava Bekker Vladimir Yarov-Yarovoy Colleen E. Clancy Yang K. Xiang Surl-Hee Ahn Igor Vorobyov |
| author_sort | Yanxiao Han |
| collection | DOAJ |
| description | Summary: G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic, and energetic mechanisms of norepinephrine (NE) and stimulatory G protein (Gs) interactions with β-adrenergic receptors (βARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within β1AR and β2AR despite identical orthosteric binding pockets. β2AR had an additional binding site, explaining variations in NE binding affinities. Simulations showed significant differences in NE dissociation pathways and receptor interactions with the Gs. β1AR binds Gs more strongly, while β2AR induces greater conformational changes in the α subunit of Gs. Furthermore, GTP and GDP binding to Gs may disrupt coupling between NE and βAR, as well as between βAR and Gs. These findings may aid in designing precise βAR-targeted drugs. |
| format | Article |
| id | doaj-art-82a62bfef4ba45648c3bc327ecf59191 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-82a62bfef4ba45648c3bc327ecf591912025-01-19T06:26:30ZengElsevieriScience2589-00422025-02-01282111741Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G proteinYanxiao Han0John R.D. Dawson1Kevin R. DeMarco2Kyle C. Rouen3Khoa Ngo4Slava Bekker5Vladimir Yarov-Yarovoy6Colleen E. Clancy7Yang K. Xiang8Surl-Hee Ahn9Igor Vorobyov10Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Corresponding authorDepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USADepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USADepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USADepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USAAmerican River College, Sacramento, CA 95841, USADepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Department of Anesthesiology and Pain Medicine, University of California, Davis, Davis, CA 95616, USA; Center for Precision Medicine and Data Science, University of California, Davis, Davis, CA 95616, USADepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Center for Precision Medicine and Data Science, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USADepartment of Pharmacology, University of California, Davis, Davis, CA 95616, USA; VA Northern California Health Care System, Mather, CA 95655, USADepartment of Chemical Engineering, University of California, Davis, Davis, CA 95616, USA; Corresponding authorDepartment of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA; Corresponding authorSummary: G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic, and energetic mechanisms of norepinephrine (NE) and stimulatory G protein (Gs) interactions with β-adrenergic receptors (βARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within β1AR and β2AR despite identical orthosteric binding pockets. β2AR had an additional binding site, explaining variations in NE binding affinities. Simulations showed significant differences in NE dissociation pathways and receptor interactions with the Gs. β1AR binds Gs more strongly, while β2AR induces greater conformational changes in the α subunit of Gs. Furthermore, GTP and GDP binding to Gs may disrupt coupling between NE and βAR, as well as between βAR and Gs. These findings may aid in designing precise βAR-targeted drugs.http://www.sciencedirect.com/science/article/pii/S2589004224029687Protein structure aspectsComputational bioinformatics |
| spellingShingle | Yanxiao Han John R.D. Dawson Kevin R. DeMarco Kyle C. Rouen Khoa Ngo Slava Bekker Vladimir Yarov-Yarovoy Colleen E. Clancy Yang K. Xiang Surl-Hee Ahn Igor Vorobyov Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein iScience Protein structure aspects Computational bioinformatics |
| title | Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein |
| title_full | Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein |
| title_fullStr | Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein |
| title_full_unstemmed | Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein |
| title_short | Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein |
| title_sort | molecular simulations reveal intricate coupling between agonist bound β adrenergic receptors and g protein |
| topic | Protein structure aspects Computational bioinformatics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224029687 |
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