ArticleMedComm2023
Cryo-EM structure of orphan G protein-coupled receptor GPR21.
Article in MedComm, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Lipid Activation of a Thalamic GPCR Extends Working Memory Time-scales.bioRxiv : the preprint server for biology · 2026Article
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Structural analysis reveals that water molecules mediate self-activation of GPR99.Communications biology · 2026Article
- Constitutively active orphan G protein-coupled receptors through the lenses of cryo-electron microscopy.The Journal of biological chemistry · 2025Review
- Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- KLF14 and SREBF-1 Binding Site Associations with Orphan Receptor Promoters in Metabolic Syndrome.International journal of molecular sciences · 2025Article
- GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.Nature structural & molecular biology · 2024Article
- Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with GCell discovery · 2024Article
- Exploring orphan GPCRs in neurodegenerative diseases.Frontiers in pharmacology · 2024Review
- Orphan G protein-coupled receptors: the ongoing search for a home.Frontiers in pharmacology · 2024Review
- An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.Nature communications · 2023Article
- Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive GNature communications · 2023Article
- GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.bioRxiv : the preprint server for biology · 2023Article
- Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GPR21 belongs to class A orphan G protein-coupled receptor (GPCR). The endogenous ligands for human GPR21 remain unidentified. GPR21 expression is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease caused by pancreatic β-cell dysfunction, decreasing insulin production, insulin resistance, and obesity. Animal studies suggested that GPR21 is a potential therapeutic target for T2DM treatment. The underlying mechanisms leading to GPR21 self-activation remain unknown. In our co-expression analysis, we noted that GPR21 could also form a stable complex with an unreported Gα protein subtype, Gαs. To gain further insights into the structural mechanisms of GPR21 activation, we employed cryo-electron microscopy (cryo-EM) and single-particle analysis to resolve the high-resolution structure of GPR21-Gαs complexes. The clear electron density map of the GPR21-Gαs provided direct evidence that GPR21 could couple to Gαs protein at physiological conditions. Thus, GPR21 might mediate previously unexplored pathways in normal or pathological conditions, which warrants further investigation. Structure-guided mutagenesis and biochemical analysis revealed that extracellular loop 2 (ECL2) of GPR21 is essential for the receptor transducing intracellular signal via cAMP. Together, the new structure data reveal a novel signaling cascade of human GPR21 mediated by ECL2 and provide fundamental information for future structure-based drug development.
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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.