ArticleThe Journal of biological chemistry2013
Inhibitory mechanism of an allosteric antibody targeting the glucagon receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study.Diabetologia · 2024Article
- Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models.The Journal of clinical investigation · 2023Article
- Computational Construction of a Single-Chain Bi-Paratopic Antibody Allosterically Inhibiting TCR-Staphylococcal Enterotoxin B Binding.Frontiers in immunology · 2021Article
- Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.Annual review of pharmacology and toxicology · 2020Review
- Perspective: The promises of a holistic view of proteins-impact on antibody engineering and drug discovery.Bioscience reports · 2019Article
- Mechanisms of signalling and biased agonism in G protein-coupled receptors.Nature reviews. Molecular cell biology · 2018Review
- Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.The Journal of biological chemistry · 2018Article
- Hepatic Gi signaling regulates whole-body glucose homeostasis.The Journal of clinical investigation · 2018Article
- Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.Genomics, proteomics & bioinformatics · 2017Article
- Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors.The Journal of biological chemistry · 2017Article
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- An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain.Cell discovery · 2016Article
- Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli.PLoS pathogens · 2015Article
- Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors.Frontiers in pharmacology · 2015Review
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Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Elevated glucagon levels and increased hepatic glucagon receptor (GCGR) signaling contribute to hyperglycemia in type 2 diabetes. We have identified a monoclonal antibody that inhibits GCGR, a class B G-protein coupled receptor (GPCR), through a unique allosteric mechanism. Receptor inhibition is mediated by the binding of this antibody to two distinct sites that lie outside of the glucagon binding cleft. One site consists of a patch of residues that are surface-exposed on the face of the extracellular domain (ECD) opposite the ligand-binding cleft, whereas the second binding site consists of residues in the αA helix of the ECD. A docking model suggests that the antibody does not occlude the ligand-binding cleft. We solved the crystal structure of GCGR ECD containing a naturally occurring G40S mutation and found a shift in the register of the αA helix that prevents antibody binding. We also found that alterations in the αA helix impact the normal function of GCGR. We present a model for the allosteric inhibition of GCGR by a monoclonal antibody that may form the basis for the development of allosteric modulators for the treatment of diabetes and other class B GPCR-related diseases.
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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.