ArticleNature communications2025
Mechanism and function of GPR3 regulated by a negative allosteric modulator.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it.
- GPR3 in neuro-metabolic-immune-reproductive nexus - a potential therapeutic target for Multi-System diseases.Annals of medicine · 2026Pooled it
- Article
- Article
- Development of pH-Sensitive β‑Adrenergic Receptor Antagonists.ACS pharmacology & translational science · 2026Article
- Discovery of Small Molecule Ligands Targeting Orphan G Protein-Coupled Receptors GPR3, GPR6, and GPR12.Journal of medicinal chemistry · 2026Review
- 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
- Mechanistic and therapeutic insights into class A GPCR dimers in neuropsychiatric disorders.npj drug discovery · 2026Review
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- GPR3 Ligands Discovered through Combined Virtual and Conformational Biosensor-Based Screening.Journal of the American Chemical Society · 2026Article
- A biased allosteric modulator functions as a molecular glue to induce βResearch square · 2025Article
- A biased allosteric modulator functions as a molecular glue to induce βbioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Allosteric modulators have gained substantial interest in current GPCR drug discovery. Here, we present a mechanism of allosteric modulation involving the dimerization of GPR3, a promising drug target for metabolic diseases and central nervous system disorders. We show that GPR3 forms constitutive homodimers in live cells and reveal that the inhibitor AF64394 functions as a negative allosteric modulator (NAM) specifically targeting dimeric GPR3. Using cryogenic electron microscopy (cryo-EM), we determine the structures of the AF64394-bound GPR3 dimer and its dimer-Gs signaling complex. These high-resolution structures reveal that AF64394 binds to the transmembrane dimer interface. AF64394 binding prevents the dissociation of the GPR3 dimer upon engagement with Gs and restrains transmembrane helix 5 in an inactive-like intermediate conformation, leading to reduced coupling with Gs. Our studies unveil a mechanism of dimer-specific inhibition of signaling with significant implications for the discovery of drugs targeting GPCRs capable of dimerization.
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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.