Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R
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 va...
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MDPI AG
2025-07-01
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| author | Marc Xu Horst Vogel Shuguang Yuan |
| author_facet | Marc Xu Horst Vogel Shuguang Yuan |
| author_sort | Marc Xu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b86a69fd798b465e8063a730c846263b |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-b86a69fd798b465e8063a730c846263b2025-08-20T03:36:27ZengMDPI AGMolecules1420-30492025-07-013015321610.3390/molecules30153216Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1RMarc Xu0Horst Vogel1Shuguang Yuan2Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, ChinaResearch Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, ChinaResearch Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, ChinaThe 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.https://www.mdpi.com/1420-3049/30/15/3216GLP-1R signalingconformational dynamicsstructural analysesmolecular dynamics simulation |
| spellingShingle | Marc Xu Horst Vogel Shuguang Yuan Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R Molecules GLP-1R signaling conformational dynamics structural analyses molecular dynamics simulation |
| title | Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R |
| title_full | Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R |
| title_fullStr | Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R |
| title_full_unstemmed | Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R |
| title_short | Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R |
| title_sort | exploring conformational transitions in biased and balanced ligand binding of glp 1r |
| topic | GLP-1R signaling conformational dynamics structural analyses molecular dynamics simulation |
| url | https://www.mdpi.com/1420-3049/30/15/3216 |
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