ArticlePLoS biology2020
Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- Somatic Genetic Rescue of Immunodeficiency in WHIM Syndrome.The New England journal of medicine · 2026Article
- Molecular basis of CXC chemokine receptor 3 ligand multispecificity.Science advances · 2026Article
- Noncanonical roles of chemokine regions in CCR9 activation revealed by structural modeling and mutational mapping.Nature communications · 2025Article
- Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.Cell · 2025Article
- Article
- Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer.bioRxiv : the preprint server for biology · 2024Article
- Structural perspectives on chemokine receptors.Biochemical Society transactions · 2024Review
- Growth factor-dependent phosphorylation of GαScience signaling · 2024Article
- Multiplex Detection of Fluorescent Chemokine Binding to CXC Chemokine Receptors by NanoBRET.International journal of molecular sciences · 2024Article
- The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12.Nature communications · 2024Article
- Discovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling.Nature communications · 2023Article
- Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis.Nature communications · 2023Article
- Article
- Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias.Science advances · 2022Article
- Mechanism of Peptide Agonist Binding in CXCR4 Chemokine Receptor.Frontiers in molecular biosciences · 2022Article
- Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization.Communications biology · 2021Article
- Advanced fluorescence microscopy reveals disruption of dynamic CXCR4 dimerization by subpocket-specific inverse agonists.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Capturing Peptide-GPCR Interactions and Their Dynamics.Molecules (Basel, Switzerland) · 2020Review
- The chemokine X-factor: Structure-function analysis of the CXC motif at CXCR4 and ACKR3.The Journal of biological chemistry · 2020Article
- Computational Study of C-X-C Chemokine Receptor (CXCR)3 Binding with Its Natural Agonists Chemokine (C-X-C Motif) Ligand (CXCL)9, 10 and 11 and with Synthetic Antagonists: Insights of Receptor Activation towards Drug Design for Vitiligo.Molecules (Basel, Switzerland) · 2020Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Chemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here, we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide cross-linking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 β1-strand, while also recapitulating earlier findings from nuclear magnetic resonance, modeling and crystallography of homologous receptors. A cross-linking-informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor targeting small molecules and biologics with novel pharmacology.
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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.