ArticleScience signaling2020
Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis.
Article in Science signaling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 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.
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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
27 citing papers in PubMed, 46 citations in OpenAlex.
- Computational Insights into the Activation Mechanism of CXCR4: Implications for the Design of Small Molecule Agonists.Journal of the American Chemical Society · 2026Article
- Elevated conformational dynamics makes ACKR3 activation-prone and G protein-incompetent.bioRxiv : the preprint server for biology · 2026Article
- Biomechanical signaling of cytoskeleton and membrane reorganization in tumor immune chemotactic migration.Theranostics · 2026Review
- Noncanonical roles of chemokine regions in CCR9 activation revealed by structural modeling and mutational mapping.Nature communications · 2025Article
- CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.Scientific reports · 2025Article
- Article
- CXC Chemokine Ligand 12 Facilitates Gi Protein Binding to CXC Chemokine Receptor 4 by Stabilizing Packing of the Proline-Isoleucine-Phenylalanine Motif: Insights from Automated Path Searching.Journal of the American Chemical Society · 2025Article
- Structural insights into CXCR4 modulation and oligomerization.Nature structural & molecular biology · 2025Article
- Growth factor-dependent phosphorylation of GαScience signaling · 2024Article
- CXCR4: from B-cell development to B cell-mediated diseases.Life science alliance · 2024Review
- Bone marrow mesenchymal stromal cells support regeneration of intestinal damage in a colitis mouse model, independent of their CXCR4 expression.Clinical and translational science · 2024Article
- Extracellular targeted protein degradation: an emerging modality for drug discovery.Nature reviews. Drug discovery · 2024Review
- CXCR4 Is a Potential Target for Anti-HIV Gene Therapy.International journal of molecular sciences · 2024Review
- NMR indicates the N-termini of PSGL1 and CCR7 bind competitively to the chemokine CCL21.Biochemistry and biophysics reports · 2023Article
- Heterodimers Are an Integral Component of Chemokine Signaling Repertoire.International journal of molecular sciences · 2023Review
- Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis.Nature communications · 2023Article
- The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention.Cellular & molecular immunology · 2023Review
- Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands.Molecules (Basel, Switzerland) · 2023Article
- A new obligate CXCL4-CXCL12 heterodimer for studying chemokine heterodimer activities and mechanisms.Scientific reports · 2022Article
- Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias.Science advances · 2022Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Because of their prominent roles in development, cancer, and HIV, the chemokine receptor CXCR4 and its ligand CXCL12 have been the subject of numerous structural and functional studies, but the determinants of ligand binding, selectivity, and signaling are still poorly understood. Here, building on our latest structural model, we used a systematic mutagenesis strategy to dissect the functional anatomy of the CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments provided evidence for pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of the predicted orientation of the chemokine relative to the receptor and providing insight into ligand selectivity. Progressive deletion of N-terminal residues revealed an unexpected contribution of the receptor N terminus to chemokine signaling. This finding challenges a longstanding "two-site" hypothesis about the essential features of the receptor-chemokine interaction in which the N terminus contributes only to binding affinity. Our results suggest that although the interaction of the chemokine N terminus with the receptor-binding pocket is the key driver of signaling, the signaling amplitude depends on the extent to which the receptor N terminus binds the chemokine. Together with systematic characterization of other epitopes, these data enable us to propose an experimentally consistent structural model for how CXCL12 binds CXCR4 and initiates signal transmission through the receptor transmembrane domain.
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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.