{"id":79365,"date":"2025-12-18T16:21:37","date_gmt":"2025-12-18T15:21:37","guid":{"rendered":"https:\/\/cri1149.mlcom-dev.net\/?post_type=publication&#038;p=79365"},"modified":"2025-12-18T16:21:42","modified_gmt":"2025-12-18T15:21:42","slug":"non-canonical-gq-activation-by-orexin-receptor-type-2-and-lemborexant-observed-in-microsecond-molecular-dynamics-simulations","status":"publish","type":"publication","link":"https:\/\/cri1149.mlcom-dev.net\/en\/publication\/non-canonical-gq-activation-by-orexin-receptor-type-2-and-lemborexant-observed-in-microsecond-molecular-dynamics-simulations\/","title":{"rendered":"Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations"},"content":{"rendered":"","protected":false},"featured_media":0,"template":"","meta":{"_acf_changed":true},"class_list":["post-79365","publication","type-publication","status-publish","hentry"],"acf":{"numero_de_publication":"Scientific Reports","date_de_publication":"20250821","numero_doi":"10.1038\/s41598-025-03857-0 ","equipe":[121],"auteurs-liste":[{"texte_libre":true,"auteur-lien":null,"auteur-text":"Paulina Dragan"},{"texte_libre":false,"auteur-lien":13082,"auteur-text":""},{"texte_libre":false,"auteur-lien":13167,"auteur-text":""},{"texte_libre":false,"auteur-lien":13053,"auteur-text":""},{"texte_libre":true,"auteur-lien":null,"auteur-text":"Dorota Latek"}],"auteurs-manuel":"","liens_externes":null,"liens":[{"lien":"https:\/\/www.nature.com\/articles\/s41598-025-03857-0"}],"paragraphe":"<h2 id=\"Abs1\" class=\"c-article-section__title js-section-title js-c-reading-companion-sections-item\" style=\"text-align: justify;\">Abstract<\/h2>\r\n<div id=\"Abs1-content\" class=\"c-article-section__content\">\r\n<p style=\"text-align: justify;\">Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep\/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX<sub>1<\/sub>) and type 2 (OX<sub>2<\/sub>), well-known drug targets in the treatment of sleep disorders,\u00a0that 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 OX<sub>2<\/sub>\u00a0in complex with the full-length G<sub>q<\/sub>\u00a0protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX<sub>2<\/sub>-selective, potent agonist compound 1 on OX<sub>2<\/sub>\u00a0activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the G\u03b1<sub>q<\/sub>\u00a0subunit. These 2\u00a0\u00b5s MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX<sub>2<\/sub>\u00a0and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition,\u00a0MD simulations of the active-state OX<sub>2<\/sub>-G<sub>q<\/sub>\u00a0complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G<sub>q<\/sub>\u00a0and to detect important micro- and macroswitches in the G\u03b1 subunit.<\/p>\r\n<\/div>","paragraphe_en":"","documents":null},"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations - CRI<\/title>\n<meta name=\"robots\" content=\"noindex, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Non-canonical Gq activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations - 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