ArticleMolecular endocrinology (Baltimore, Md.)2011
Residues within the transmembrane domain of the glucagon-like peptide-1 receptor involved in ligand binding and receptor activation: modelling the ligand-bound receptor.
Article in Molecular endocrinology (Baltimore, Md.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 52 citations in OpenAlex.
- All roads lead to Rome: Emergence of Mechanistic Divergence Shapes Activation of Class B1 G-Protein Coupled Receptors.bioRxiv : the preprint server for biology · 2026Article
- Expression and functional diversity of the glucagon-like peptide-1 receptor across tumor types.Discover oncology · 2025Article
- Investigating Potential GLP-1 Receptor Agonists in Cyclopeptides fromMetabolites · 2022Article
- A Paradigm for Peptide Hormone-GPCR Analyses.Molecules (Basel, Switzerland) · 2020Review
- Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.The Journal of biological chemistry · 2018Article
- Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.Nature · 2018Article
- Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.Genomics, proteomics & bioinformatics · 2017Article
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- Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R).The Journal of biological chemistry · 2017Article
- Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor.Biochemical pharmacology · 2016Article
- Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.Pharmacological reviews · 2016Review
- Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R).The Journal of biological chemistry · 2016Article
- Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.Scientific reports · 2016Article
- A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures.Molecular pharmacology · 2016Article
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- The peptide agonist-binding site of the glucagon-like peptide-1 (GLP-1) receptor based on site-directed mutagenesis and knowledge-based modelling.Bioscience reports · 2015Article
- Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).The Journal of biological chemistry · 2015Article
- Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide.World journal of diabetes · 2015Review
- Ligand binding pocket formed by evolutionarily conserved residues in the glucagon-like peptide-1 (GLP-1) receptor core domain.The Journal of biological chemistry · 2015Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9-39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9-39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.