ArticleThe Journal of biological chemistry2016
Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 72 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- GPCRVS - AI-driven Decision Support System for GPCR Virtual Screening.International journal of molecular sciences · 2025Article
- Key Interaction Changes Determine the Activation Process of Human Parathyroid Hormone Type 1 Receptor.Journal of the American Chemical Society · 2025Article
- Research progress on oral glucagon-like peptide-1 receptor agonists in the treatment of diabetes mellitus type 2.Frontiers in molecular biosciences · 2025Review
- Decoding migraine disorders: parathyroid hormone-related peptide receptors as key genetic drivers.Brain communications · 2025Article
- Insights into the structure and activation mechanism of some class B1 GPCR family members.Molecular biology reports · 2024Review
- Baicalein: A potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement.Journal of pharmaceutical analysis · 2024Article
- Molecular basis of signal transduction mediated by the human GIPR splice variants.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR.iScience · 2023Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Article
- High glucose-induced glucagon resistance and membrane distribution of GCGR revealed by super-resolution imaging.iScience · 2023Article
- GLP1R rs3765467 Polymorphism Is Associated with the Risk of Early Onset Type 2 Diabetes.International journal of endocrinology · 2023Article
- Article
- Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.Nature communications · 2022Article
- Modulating effects of RAMPs on signaling profiles of the glucagon receptor family.Acta pharmaceutica Sinica. B · 2022Article
- Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.Nature communications · 2021Article
- A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.Cell research · 2020Article
- Structural basis for activation of the growth hormone-releasing hormone receptor.Nature communications · 2020Article
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation.
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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.