Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
| العنوان: | Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation |
|---|---|
| المؤلفون: | Lachlan Clydesdale, Hari Venugopal, Peishen Zhao, Patrick M. Sexton, Alisa Glukhova, Arthur Christopoulos, Christopher A. Reynolds, Yi Lynn Liang, Xin Zhang, Tin T. Truong, Andrew N. Keller, Maryam Khoshouei, Matthew J. Belousoff, Karen J. Gregory, Giuseppe Deganutti, Radostin Danev, Denise Wootten, Katie Leach |
| المصدر: | Nature Communications, Vol 13, Iss 1, Pp 1-18 (2022) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Protein Conformation, alpha-Helical, Gene Expression, General Physics and Astronomy, Peptide, Ligands, chemistry.chemical_compound, Receptor pharmacology, G protein-coupled receptors, Glucagon-Like Peptide 1, Cloning, Molecular, Receptor, chemistry.chemical_classification, Multidisciplinary, digestive, oral, and skin physiology, Recombinant Proteins, Transmembrane domain, Oxyntomodulin, Baculoviridae, hormones, hormone substitutes, and hormone antagonists, Protein Binding, Agonist, endocrine system, medicine.drug_class, G protein, Science, Genetic Vectors, Allosteric regulation, Molecular Dynamics Simulation, Glucagon-Like Peptide-1 Receptor, Article, General Biochemistry, Genetics and Molecular Biology, Structure-Activity Relationship, Allosteric Regulation, Electron microscopy, medicine, Humans, Protein Interaction Domains and Motifs, Binding Sites, Cryoelectron Microscopy, Mutagenesis, General Chemistry, Kinetics, HEK293 Cells, chemistry, Mutation, Biophysics, Exenatide, Protein Conformation, beta-Strand |
| الوصف: | The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists. The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f5aa9dcac923a091ce55a4b69969de5 https://doaj.org/article/8f7e8894b23a4f8eb32f5d2c26ccefc6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6f5aa9dcac923a091ce55a4b69969de5 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20411723 |
|---|