ArticleNature communications2022
Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- Article
- NicheTrans: spatial-aware cross-omics translation.Nature methods · 2026Article
- International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors.Pharmacological reviews · 2026Review
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Molecular insights into ligand recognition and signaling of OXGR1.Nature communications · 2025Article
- Constitutively active orphan G protein-coupled receptors through the lenses of cryo-electron microscopy.The Journal of biological chemistry · 2025Review
- Orphan G Protein-Coupled Receptor GPR88: Mapping Its Significance in Central Nervous System Disorders.Molecular neurobiology · 2025Review
- Identification of a Subpopulation of Astrocyte Progenitor Cells in the Neonatal Subventricular Zone: Evidence that Migration is Regulated by Glutamate Signaling.Neurochemical research · 2025Article
- Intracellular GPCR modulators enable precision pharmacology.npj drug discovery · 2025Review
- GPR88 promotes neurite outgrowth of sensory neurons via activation of GFrontiers in pharmacology · 2025Article
- Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches.Current issues in molecular biology · 2024Review
- Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.Science advances · 2024Article
- The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer.Nature communications · 2024Article
- Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator.Nature communications · 2024Article
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Structural and functional characterization of the endogenous agonist for orphan receptor GPR3.Cell research · 2024Article
- Design, Synthesis, and Structure-Activity Relationship Studies of Novel GPR88 Agonists (4-Substituted-phenyl)acetamides Based on the Reversed Amide Scaffold.ACS chemical neuroscience · 2024Article
- Orphan G protein-coupled receptors: the ongoing search for a home.Frontiers in pharmacology · 2024Review
- The activation mechanism and antibody binding mode for orphan GPR20.Cell discovery · 2023Article
- Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation.Journal of medicinal chemistry · 2023Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GPR88 is an orphan class A G-protein-coupled receptor that is highly expressed in the striatum and regulates diverse brain and behavioral functions. Here we present cryo-EM structures of the human GPR88-Gi1 signaling complex with or without a synthetic agonist (1R, 2R)-2-PCCA. We show that (1R, 2R)-2-PCCA is an allosteric modulator binding to a herein identified pocket formed by the cytoplasmic ends of transmembrane segments 5, 6, and the extreme C terminus of the α5 helix of Gi1. We also identify an electron density in the extracellular orthosteric site that may represent a putative endogenous ligand of GPR88. These structures, together with mutagenesis studies and an inactive state model obtained from metadynamics simulations, reveal a unique activation mechanism for GPR88 with a set of distinctive structure features and a water-mediated polar network. Overall, our results provide a structural framework for understanding the ligand binding, activation and signaling mechanism of GPR88, and will facilitate the innovative drug discovery for neuropsychiatric disorders and for deorphanization of this receptor.
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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.