{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:05:26Z","timestamp":1791558326499,"version":"4.3.4"},"reference-count":64,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AlphaMol-SIAT joint laboratory"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The glucagon-like peptide-1 receptor (GLP-1R), which belongs to the class B1 G protein-coupled receptor (GPCR) family, is an important target for treatment of metabolic disorders, including type 2 diabetes and obesity. The growing interest in GLP-1R-based therapies is driven by the development of various functional agonists as well as the huge commercial market. Thus, understanding the structural details of ligand-induced signaling are important for developing improved GLP-1R drugs. Here, we investigated the conformational dynamics of the receptor in complex with a selection of prototypical functional agonists, including CHU-128 (small molecule-biased), danuglipron (small molecule balanced), and Peptide 19 (peptide balanced), which exhibit unique, distinct binding modes and induced helix packing. Furthermore, our all-atom molecular dynamics (MD) simulations revealed atomic feature how different those ligands led to signaling pathway preference. Our findings offer valuable insights into the mechanistic principle of GLP-1R activation, which are helpful for the rational design of next-generation GLP-1R drug molecules.<\/jats:p>","DOI":"10.3390\/molecules30153216","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T13:11:11Z","timestamp":1754313071000},"page":"3216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9158-8528","authenticated-orcid":false,"given":"Marc","family":"Xu","sequence":"first","affiliation":[{"name":"Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Vogel","sequence":"additional","affiliation":[{"name":"Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen 518055, China"},{"name":"Institut des Sciences et Ing\u00e9nierie Chimiques (ISIC), Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9858-4742","authenticated-orcid":false,"given":"Shuguang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"AlphaMol Science Ltd., Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/s41594-021-00674-7","article-title":"GPCR Activation Mechanisms across Classes and Macro\/Microscales","volume":"28","author":"Hauser","year":"2021","journal-title":"Nat. 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