ArticleProceedings of the National Academy of Sciences of the United States of America2012
Molecular basis for negative regulation of the glucagon receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 127 citations in OpenAlex.
- Single-Molecule Insights into GPCR Conformational Landscapes.The Journal of membrane biology · 2025Review
- Antibodies expand the scope of angiotensin receptor pharmacology.Nature chemical biology · 2024Article
- Review
- Glucagon and Its Receptors in the Mammalian Heart.International journal of molecular sciences · 2023Review
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Article
- Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.ACS medicinal chemistry letters · 2022Article
- Dynamic mRNA and miRNA expression of the head during early development in bighead carp (Hypophthalmichthys nobilis).BMC genomics · 2022Article
- Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion.Frontiers in endocrinology · 2022Review
- Proteolytic Cleavage of the Extracellular Domain Affects Signaling of Parathyroid Hormone 1 Receptor.Frontiers in endocrinology · 2022Article
- Article
- Mechanisms of adhesion G protein-coupled receptor activation.The Journal of biological chemistry · 2020Review
- Synthetic nanobodies as angiotensin receptor blockers.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural insights into differences in G protein activation by family A and family B GPCRs.Science (New York, N.Y.) · 2020Article
- The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor.Biophysical journal · 2020Article
- A combined activation mechanism for the glucagon receptor.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Full-length human GLP-1 receptor structure without orthosteric ligands.Nature communications · 2020Article
- Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.Annual review of pharmacology and toxicology · 2020Review
- Structure-guided discovery of a single-domain antibody agonist against human apelin receptor.Science advances · 2020Article
- High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist.Nature structural & molecular biology · 2018Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.
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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.