Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations
Abstract Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX1) and type 2 (OX2), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a sign...
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Nature Portfolio
2025-08-01
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| author | Paulina Dragan Valerie Gratio Thierry Voisin Alain Couvineau Dorota Latek |
| author_facet | Paulina Dragan Valerie Gratio Thierry Voisin Alain Couvineau Dorota Latek |
| author_sort | Paulina Dragan |
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| description | Abstract Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX1) and type 2 (OX2), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX2 in complex with the full-length Gq protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX2-selective, potent agonist compound 1 on OX2 activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gαq subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX2 and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX2-Gq complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of Gq and to detect important micro- and macroswitches in the Gα subunit. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-08-01 |
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| spelling | doaj-art-3a1fb40771554a2ca7590820c77167d02025-08-24T11:20:48ZengNature PortfolioScientific Reports2045-23222025-08-0115111310.1038/s41598-025-03857-0Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulationsPaulina Dragan0Valerie Gratio1Thierry Voisin2Alain Couvineau3Dorota Latek4Faculty of Chemistry, University of WarsawINSERM UMR1149/Inflammation Research Center (CRI), Université Paris Cité, Team “From Inflammation to Cancer in Digestive Diseases (INDiD)”, DHU UNITYINSERM UMR1149/Inflammation Research Center (CRI), Université Paris Cité, Team “From Inflammation to Cancer in Digestive Diseases (INDiD)”, DHU UNITYINSERM UMR1149/Inflammation Research Center (CRI), Université Paris Cité, Team “From Inflammation to Cancer in Digestive Diseases (INDiD)”, DHU UNITYFaculty of Chemistry, University of WarsawAbstract Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX1) and type 2 (OX2), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX2 in complex with the full-length Gq protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX2-selective, potent agonist compound 1 on OX2 activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gαq subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX2 and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX2-Gq complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of Gq and to detect important micro- and macroswitches in the Gα subunit.https://doi.org/10.1038/s41598-025-03857-0Orexin receptorsOX2Gq protein activationGDP/GTP exchangeSignal transductionLemborexant |
| spellingShingle | Paulina Dragan Valerie Gratio Thierry Voisin Alain Couvineau Dorota Latek Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations Scientific Reports Orexin receptors OX2 Gq protein activation GDP/GTP exchange Signal transduction Lemborexant |
| title | Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| title_full | Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| title_fullStr | Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| title_full_unstemmed | Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| title_short | Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| title_sort | non canonical gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations |
| topic | Orexin receptors OX2 Gq protein activation GDP/GTP exchange Signal transduction Lemborexant |
| url | https://doi.org/10.1038/s41598-025-03857-0 |
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