ArticleThe Journal of biological chemistry2017
Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Insights into the structure and activation mechanism of some class B1 GPCR family members.Molecular biology reports · 2024Review
- Article
- Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome.Communications biology · 2023Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling.Nature communications · 2022Article
- A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2.Nature communications · 2022Article
- Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor.Computational and structural biotechnology journal · 2022Article
- Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.Nature communications · 2021Article
- Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.Nature communications · 2021Article
- Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors.Frontiers in molecular biosciences · 2021Article
- Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy.Nature communications · 2020Article
- Structural insights into emergent signaling modes of G protein-coupled receptors.The Journal of biological chemistry · 2020Review
- Structural insights into differences in G protein activation by family A and family B GPCRs.Science (New York, N.Y.) · 2020Article
- An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2020Article
- Ligand-induced activation of ERK1/2 signaling by constitutively active GActa pharmacologica Sinica · 2019Article
- Structure and dynamics of the active human parathyroid hormone receptor-1.Science (New York, N.Y.) · 2019Article
- Structural biology of G protein-coupled receptor signaling complexes.Protein science : a publication of the Protein Society · 2019Review
- Proton Sensitivity of Corticotropin-Releasing Hormone Receptor 1 Signaling to Proopiomelanocortin in Male Mice.Endocrinology · 2019Article
- Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.The Journal of biological chemistry · 2018Article
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
The glucagon receptor (GCGR) belongs to the secretin-like (class B) family of G protein-coupled receptors (GPCRs) and is activated by the peptide hormone glucagon. The structures of an activated class B GPCR have remained unsolved, preventing a mechanistic understanding of how these receptors are activated. Using a combination of structural modeling and mutagenesis studies, we present here two modes of ligand-independent activation of GCGR. First, we identified a GCGR-specific hydrophobic lock comprising Met-338 and Phe-345 within the IC3 loop and transmembrane helix 6 (TM6) and found that this lock stabilizes the TM6 helix in the inactive conformation. Disruption of this hydrophobic lock led to constitutive G protein and arrestin signaling. Second, we discovered a polar core comprising conserved residues in TM2, TM3, TM6, and TM7, and mutations that disrupt this polar core led to constitutive GCGR activity. On the basis of these results, we propose a mechanistic model of GCGR activation in which TM6 is held in an inactive conformation by the conserved polar core and the hydrophobic lock. Mutations that disrupt these inhibitory elements allow TM6 to swing outward to adopt an active TM6 conformation similar to that of the canonical β
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Registered trials
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.