ArticleNature2016
Intracellular allosteric antagonism of the CCR9 receptor.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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
138 citing papers in PubMed, 270 citations in OpenAlex.
- Patterns of Immune Activation in HIV and Non HIV Subjects and Its Relation to Cardiovascular Disease Risk.Frontiers in immunology · 2021Trial
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- Nano-GAngewandte Chemie (International ed. in English) · 2026Article
- A novel fusion tool to enable G protein-coupled receptor structure determination.Acta crystallographica. Section D, Structural biology · 2026Article
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Molecular mechanisms for subtype selectivity of kinin receptors' antagonists.Nature communications · 2026Article
- Structure basis for C-C chemokine receptor 4 modulation by orthosteric and allosteric antagonists.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Enhancing Magnetic Hyperthermia at the Cell Membrane by Anchoring 92R-Functionalized Magnetic Nanoparticles to Low-Endocytic CCR9 Surface Receptors.Advanced healthcare materials · 2026Article
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- Lymphocyte homing disorder: a concealed driver of intestinal immune collapse in sepsis.Frontiers in immunology · 2026Review
- Epitope analysis of an anti-mouse CCR1 monoclonal antibody S15040E using flow cytometry.Biochemistry and biophysics reports · 2025Article
- Noncanonical roles of chemokine regions in CCR9 activation revealed by structural modeling and mutational mapping.Nature communications · 2025Article
- Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine DACS chemical neuroscience · 2025Article
- Structural Insights into the ADCC Mechanism and Resistance of Mogamulizumab, a First-in-Class Anti-CCR4 Therapy for Cutaneous T Cell Lymphoma.International journal of molecular sciences · 2025Article
- Molecular mechanism of the arrestin-biased agonism of neurotensin receptor 1 by an intracellular allosteric modulator.Cell research · 2025Article
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7.Journal of medicinal chemistry · 2025Article
- Progress in structure-based drug development targeting chemokine receptors.Frontiers in pharmacology · 2025Review
- Molecular basis for chemokine recognition and activation of XCR1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
78 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases. Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization. The high failure rate may in part be due to limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information. CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease. The selective CCR9 antagonist vercirnon progressed to phase 3 clinical trials in Crohn's disease but efficacy was limited, with the need for very high doses to block receptor activation. Here we report the crystal structure of the CCR9 receptor in complex with vercirnon at 2.8 Å resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.
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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.