GO:0031730 CCR5 chemokine receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031730 (CCR5 chemokine receptor binding) is a molecular_function term defined as binding to a CCR5 chemokine receptor.
• CCR5 is a seven-transmembrane chemokine receptor whose ligand-binding activity depends on the receptor's N-terminal sulfation and the membrane cholesterol environment.
• Structural and computational studies have resolved how chemokines and small-molecule inhibitors engage the CCR5 binding pocket, informing anti-HIV drug design.
• CCR5 ligand-binding properties are heterogeneous across cell-surface subpopulations because of differential tyrosine sulfation, creating distinct receptor pools with different affinities.
• CCR5 and its ligands are implicated in inflammatory diseases such as rheumatoid arthritis, where a pathologically expanded peripheral T helper cell subset drives B cell responses.
• Researchers study GO:0031730 using binding assays, structural biology, site-directed mutagenesis, and CRISPR-engineered cell models to dissect ligand-receptor interactions.
Description
GO:0031730, CCR5 chemokine receptor binding, is a Gene Ontology molecular_function term that describes the binding of a ligand to the CCR5 chemokine receptor. CCR5 (C-C chemokine receptor type 5) is a member of the chemokine receptor family and functions as a seven-transmembrane G protein-coupled receptor that recognizes inflammatory CC chemokines. The term captures the molecular recognition event at the receptor surface, which is the first step in CCR5-mediated signaling and is central to immune cell trafficking and host defense. Because CCR5 is also the principal co-receptor for macrophage-tropic HIV-1 entry, understanding its ligand-binding properties has direct therapeutic relevance. Researchers studying GO:0031730 aim to define how chemokines, modified chemokines, and small-molecule inhibitors engage the receptor, and how post-translational modifications and membrane lipids tune this interaction. The binding event is not a simple lock-and-key process: the CCR5 N-terminus, extracellular loops, and the lipid bilayer all contribute to ligand recognition, and structural studies have begun to resolve these contributions at near-atomic resolution. Consequently, GO:0031730 sits at the intersection of chemokine biology, structural pharmacology, and HIV pathogenesis research.
CCR5 chemokine receptor binding At A Glance
| GO ID | GO:0031730 |
|---|---|
| GO term | CCR5 chemokine receptor binding |
| Ontology | molecular_function |
| Synonym | CCR5 chemokine receptor ligand |
| Definition | Binding to a CCR5 chemokine receptor |
| Major function | Mediates ligand recognition at the CCR5 receptor surface, initiating chemokine signaling and contributing to HIV-1 co-receptor engagement |
| Related receptor | CCR5 (C-C chemokine receptor type 5), a seven-transmembrane GPCR |
| Key ligands | CC chemokines such as CCL3, CCL4, and CCL5, as well as engineered or small-molecule inhibitors |
| Modification dependence | Ligand binding is modulated by CCR5 tyrosine sulfation and membrane cholesterol |
What Is GO:0031730?
In the Gene Ontology, GO:0031730 (CCR5 chemokine receptor binding) is defined as the binding to a CCR5 chemokine receptor. It is a molecular_function term, meaning it describes an activity rather than a process or location. The synonym CCR5 chemokine receptor ligand indicates that the term is used for gene products that act as ligands or binding partners of CCR5. This binding activity is distinct from receptor activation or downstream signaling; it specifically denotes the physical interaction between a ligand and the CCR5 receptor.
Why Is CCR5 chemokine receptor binding Important in Cell Biology?
GO:0031730 is important because the binding of ligands to CCR5 is the molecular trigger for chemokine-mediated immune cell recruitment and because CCR5 is a validated drug target in HIV-1 infection and inflammatory disease. The affinity and selectivity of this binding event determine whether CCR5 signals in response to natural chemokines or is blocked by antagonists, making it a focal point for antiviral and anti-inflammatory therapeutic development. In addition, the receptor's binding properties are shaped by post-translational modifications and the lipid environment, which has implications for how cells tune their responsiveness to chemokines.
• CCR5 ligand binding is the first step in chemokine-driven leukocyte recruitment and immune surveillance.
• CCR5 is a major co-receptor for HIV-1 entry, and its ligand-binding pocket is a target for entry inhibitors.
• Differential tyrosine sulfation of CCR5 generates cell-surface subpopulations with distinct ligand-binding properties.
• Membrane cholesterol directly impacts CCR5 ligand-binding activity, linking lipid composition to receptor function.
• Structural analysis of chemokine receptor-ligand interactions guides rational drug design for CCR5 antagonists.
• CCR5 and its ligands are implicated in autoimmune and inflammatory conditions such as rheumatoid arthritis.
• Computational and in vitro approaches have identified novel CCR5 inhibitors with improved binding efficacy.
• Glycosylation and sulfation create a 'glyco-sulfo barcode' that regulates chemokine receptor function.
• Understanding GO:0031730 helps interpret how natural chemokines compete with therapeutic antagonists.
• CRISPR-engineered cell models enable causal testing of CCR5 ligand-binding determinants.
Molecular Mechanism of CCR5 chemokine receptor binding
Ligand recognition at the CCR5 N-terminus and extracellular loops
In simple terms: The receptor grabs the chemokine using its flexible outer tail and loops.
CCR5 is a seven-transmembrane chemokine receptor, and its N-terminal domain and extracellular loops form the primary ligand recognition surface. Structural and mutational studies show that chemokines engage the receptor through a two-step mechanism in which the chemokine core first docks onto the receptor N-terminus, followed by insertion of the chemokine N-loop into the transmembrane binding pocket. This interaction is the molecular basis of GO:0031730, the binding activity annotated to CCR5 ligands.
Role of tyrosine sulfation in ligand binding
In simple terms: Adding sulfate groups to the receptor's tail changes how tightly it holds chemokines.
Tyrosine sulfation of the CCR5 N-terminus is a critical determinant of ligand binding. Scurci et al. demonstrated that CCR5 tyrosine sulfation heterogeneity generates cell surface receptor subpopulations with different ligand binding properties, meaning that the same receptor can exist in states with distinct affinities. This modification is part of a broader 'glyco-sulfo barcode' that regulates chemokine receptor function. Consequently, GO:0031730 activity is not uniform across all CCR5 molecules on a cell.
Membrane cholesterol and lipid environment
In simple terms: The fat around the receptor acts like a dial that tunes how well it binds ligands.
Cholesterol impacts chemokine CCR5 receptor ligand-binding activity, as shown by Calmet et al., who found that the lipid environment modulates the receptor's ability to bind ligands. This indicates that GO:0031730 is sensitive to membrane composition, and that cholesterol depletion or enrichment can alter binding. The lipid bilayer therefore acts as an allosteric regulator of CCR5 ligand recognition.
Structural basis of chemokine recognition and inhibitor binding
In simple terms: Scientists have taken detailed pictures of the receptor to see exactly how ligands fit.
Zhang et al. resolved the structural basis for chemokine recognition and receptor activation of CCR5, providing atomic-level insight into how ligands occupy the binding pocket. Arimont et al. analyzed chemokine receptor-ligand interactions across the family, highlighting conserved and divergent features of CCR5 binding. These structures explain how natural chemokines and small-molecule inhibitors compete for the same or overlapping sites, which is directly relevant to GO:0031730.
Inhibitor design and binding efficacy
In simple terms: New drugs are being designed to block the receptor by fitting into its binding pocket.
Kumar et al. characterized CB-0821, a novel CCR5 inhibitor with improved binding efficacy proposed as an anti-HIV candidate, using computational and in vitro approaches. This work exemplifies how understanding GO:0031730 can guide the development of antagonists that prevent ligand binding and viral entry. Oppermann's review provides a broader framework for CCR5 structure, function, and regulation, which is essential for interpreting inhibitor binding data.
Key Genes Involved in GO:0031730 CCR5 chemokine receptor binding
The following genes and proteins are directly or indirectly involved in CCR5 chemokine receptor binding (GO:0031730) and its regulation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCR5 | Seven-transmembrane chemokine receptor that binds CC chemokines; the receptor in GO:0031730 | Core receptor for ligand-binding assays, structural studies, and HIV-1 co-receptor research |
| CCL3 | Natural ligand of CCR5; binds the receptor to trigger signaling | Used to study chemokine recognition and competition with inhibitors |
| CCL4 | Natural ligand of CCR5; binds the receptor and modulates immune cell recruitment | Common ligand in binding assays and structural studies |
| CCL5 | Natural ligand of CCR5; high-affinity binder and major inflammatory chemokine | Frequently used to probe CCR5 ligand-binding activity and sulfation effects |
| TPST1 | Tyrosylprotein sulfotransferase that sulfates CCR5 N-terminal tyrosines | Modulates CCR5 ligand-binding heterogeneity and glyco-sulfo barcode |
| TPST2 | Tyrosylprotein sulfotransferase involved in CCR5 sulfation | Contributes to receptor subpopulations with different binding properties |
| CHST | Carbohydrate sulfotransferase contributing to glyco-sulfo modifications | Part of the glyco-sulfo barcode regulating chemokine receptor function |
| GNAI1 | G protein alpha subunit downstream of CCR5 activation | Links ligand binding to intracellular signaling |
| GNAI2 | G protein alpha subunit mediating CCR5 signaling | Readout of functional consequences of ligand binding |
| GNAI3 | G protein alpha subunit in chemokine receptor signaling | Used to dissect post-binding signaling events |
| ARRB1 | Beta-arrestin involved in CCR5 desensitization after ligand binding | Regulates receptor trafficking following GO:0031730 activity |
| ARRB2 | Beta-arrestin involved in CCR5 internalization | Modulates receptor availability for ligand binding |
| GRK2 | G protein-coupled receptor kinase that phosphorylates activated CCR5 | Regulates desensitization after ligand engagement |
| GRK3 | G protein-coupled receptor kinase acting on CCR5 | Contributes to receptor regulation post-binding |
| CD4 | Primary HIV-1 receptor that cooperates with CCR5 | Required for viral entry assays that depend on CCR5 ligand-binding pocket |
| PTPRC | CD45 phosphatase that can modulate chemokine receptor signaling | Marker of T helper cell subsets in inflammatory disease |
| CXCR5 | Related chemokine receptor used as a comparison for CCR5 binding | Helps contextualize CCR5 ligand-binding specificity |
| PDCD1 | PD-1, a marker of the expanded T helper subset in rheumatoid arthritis | Links CCR5 biology to inflammatory disease models |
How Is CCR5 chemokine receptor binding Regulated?
CCR5 chemokine receptor binding (GO:0031730) is regulated at multiple levels. Tyrosine sulfation of the receptor N-terminus by tyrosylprotein sulfotransferases generates heterogeneous receptor subpopulations with different ligand-binding properties. Membrane cholesterol content directly impacts CCR5 ligand-binding activity, so changes in lipid composition can enhance or reduce binding. At the receptor level, phosphorylation by G protein-coupled receptor kinases and recruitment of beta-arrestins regulate desensitization and internalization after ligand engagement, thereby controlling the availability of CCR5 for subsequent binding events. These layers of regulation ensure that GO:0031730 activity is tuned to the cellular context.
CCR5 chemokine receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCR5 | HIV-1 co-receptor binding and viral entry | CCR5 knockout or point-mutant cell lines for viral entry assays |
| CCL5 | Inflammatory chemokine signaling in immune disorders | Overexpression or knockout of CCL5 in immune cell models |
| TPST1/TPST2 | Altered CCR5 sulfation and ligand-binding heterogeneity | Knockout of sulfotransferases to test binding subpopulations |
| CCR5 | Rheumatoid arthritis T helper cell expansion | Patient-derived T cell models with CCR5 perturbation |
| CCR5 | Cholesterol-dependent ligand binding in membranes | Cholesterol-modulated cell culture and binding assays |
HIV-1 infection and CCR5 co-receptor binding
CCR5 is a principal co-receptor for macrophage-tropic HIV-1, and the virus engages the same receptor surface that mediates chemokine binding. Inhibitors such as CB-0821 have been designed to block this interaction with improved binding efficacy, highlighting the therapeutic importance of GO:0031730. Structural studies of chemokine recognition and receptor activation provide a template for understanding how viral entry and drug blockade intersect at the ligand-binding pocket.
Rheumatoid arthritis and inflammatory T cell subsets
Rao et al. identified a pathologically expanded peripheral T helper cell subset that drives B cells in rheumatoid arthritis, a subset marked by chemokine receptor expression including CCR5-related biology. Chemokine receptor-ligand interactions, including those described by GO:0031730, contribute to the recruitment and positioning of such pathogenic T cells in inflamed tissue. This links CCR5 ligand binding to autoimmune disease pathogenesis.
Inflammatory and immune-mediated disorders
Because CCR5 binding of CC chemokines is a central step in leukocyte trafficking, dysregulated GO:0031730 activity can contribute to chronic inflammation. The glyco-sulfo barcode that regulates chemokine receptor function adds another layer of disease-relevant heterogeneity. Cholesterol-dependent modulation of CCR5 ligand binding further connects lipid metabolism to inflammatory disease mechanisms.
From CCR5 chemokine receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of CCR5 abolish ligand binding? | CCR5 knockout cell line |
| Which tyrosine residues are required for sulfation-dependent binding? | Point-mutation knock-in of CCR5 N-terminal tyrosines |
| How does a disease-associated CCR5 variant alter ligand affinity? | Knock-in of the variant into an endogenous locus |
| Where is CCR5 ligand binding localized on the cell surface? | Tagged knock-in of CCR5 with a fluorescent tag |
| Does overexpression of CCL5 change CCR5 binding dynamics? | CCL5 overexpression cell model |
| Can a candidate inhibitor block CCR5 ligand binding? | Wild-type CCR5 cells treated with inhibitor in binding assays |
How to Study the CCR5 chemokine receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding assay | Direct ligand-receptor binding affinity | Screening CCR5 inhibitors and chemokine competition |
| Surface plasmon resonance | Real-time binding kinetics | Comparing chemokine affinities for CCR5 |
| Cryo-EM / X-ray crystallography | Atomic structure of receptor-ligand complex | Visualizing the CCR5 binding pocket |
| Site-directed mutagenesis | Effect of specific residues on binding | Testing tyrosine sulfation sites in CCR5 |
| Flow cytometry | Cell-surface receptor levels and ligand binding | Analyzing CCR5 subpopulations on T cells |
| Computational docking | Predicted ligand poses and binding energy | Virtual screening of CCR5 inhibitors |
| Cholesterol modulation assays | Lipid-dependent changes in binding | Testing membrane environment effects on CCR5 |
| Glyco-sulfo modification analysis | Post-translational modification status | Linking sulfation/glycosylation to receptor function |
Ligand-binding assays
Direct binding assays using labeled chemokines or inhibitors are the primary method to measure GO:0031730 activity. These assays can quantify affinity, competition, and the effects of cholesterol or sulfation on binding. Kumar et al. used computational and in vitro binding approaches to evaluate a novel CCR5 inhibitor.
Structural biology and computational modeling
X-ray crystallography, cryo-electron microscopy, and molecular modeling reveal how ligands occupy the CCR5 binding pocket. Zhang et al. resolved the structural basis for chemokine recognition and receptor activation, while Arimont et al. provided a comparative structural analysis of chemokine receptor-ligand interactions. These methods explain the atomic details of GO:0031730.
Site-directed mutagenesis and post-translational modification analysis
Mutating N-terminal tyrosines or enzymes involved in sulfation allows researchers to test how post-translational modifications affect ligand binding. Scurci et al. used such approaches to demonstrate that CCR5 tyrosine sulfation heterogeneity generates subpopulations with different binding properties. Glyco-sulfo barcode studies further show the importance of these modifications.
Cell-based signaling and imaging
Downstream signaling assays and imaging can be used to confirm that ligand binding leads to functional consequences. Beta-arrestin recruitment, G protein activation, and receptor internalization are common readouts. In disease contexts, flow cytometry and imaging of T cell subsets can link CCR5 biology to pathology.
How CRISPR Can Be Used to Study GO:0031730 CCR5 chemokine receptor binding
Knockout
CRISPR knockout of CCR5 or its modifying enzymes (e.g., TPST1/TPST2) can abolish or alter ligand binding, providing a clean background to test GO:0031730 activity. CCR5 knockout cell lines are widely used to study HIV-1 co-receptor dependence and chemokine signaling.
Point Mutation
Point mutations can be introduced into the CCR5 N-terminus to test which tyrosine residues are required for sulfation-dependent ligand binding. Such models help dissect the heterogeneity of receptor subpopulations described by Scurci et al..
Knock-in
Knock-in of tagged or variant CCR5 alleles allows researchers to track receptor localization and binding in a native context. This is useful for studying disease-associated variants and their impact on ligand affinity.
Overexpression
Overexpression of CCR5 or its ligands (CCL3, CCL4, CCL5) can amplify binding signals for biochemical assays and screening. Overexpression models are also used to study how excess ligand affects receptor occupancy and downstream signaling.
How EDITGENE Supports CCR5 chemokine receptor binding Research
Researchers studying CCR5 chemokine receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand recognition, receptor regulation, or disease-associated phenotypes. EDITGENE provides CRISPR-based cell model services that enable precise genetic perturbations to test these hypotheses in relevant cell types.
Contact EDITGENE today to design your custom CRISPR model for CCR5 chemokine receptor binding research.
Frequently Asked Questions About CCR5 chemokine receptor binding
What is GO:0031730?
GO:0031730 is the Gene Ontology molecular_function term for CCR5 chemokine receptor binding, defined as binding to a CCR5 chemokine receptor.
What is CCR5 chemokine receptor binding?
It is the physical interaction between a ligand and the CCR5 receptor, the first step in chemokine signaling and a key event in HIV-1 co-receptor engagement.
What genes are involved in CCR5 chemokine receptor binding?
Key genes include CCR5 itself, its ligands CCL3, CCL4, and CCL5, and modifying enzymes such as TPST1 and TPST2.
How is CCR5 ligand binding regulated?
It is regulated by tyrosine sulfation, membrane cholesterol, and receptor desensitization machinery such as GRKs and beta-arrestins.
Why is CCR5 ligand binding important for HIV?
CCR5 is a principal co-receptor for HIV-1, and blocking its ligand-binding pocket prevents viral entry.
What methods study CCR5 chemokine receptor binding?
Common methods include radioligand binding assays, surface plasmon resonance, cryo-EM, mutagenesis, and computational docking.
Does cholesterol affect CCR5 binding?
Yes, cholesterol impacts chemokine CCR5 receptor ligand-binding activity, so membrane composition can tune binding.
What is the role of tyrosine sulfation in CCR5 binding?
Tyrosine sulfation of the CCR5 N-terminus generates receptor subpopulations with different ligand-binding properties.
Which diseases are linked to CCR5 ligand binding?
HIV-1 infection, rheumatoid arthritis, and other inflammatory disorders are linked to CCR5 ligand-binding biology.
How can CRISPR help study CCR5 chemokine receptor binding?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal testing of genes involved in CCR5 ligand binding.
Conclusion
GO:0031730 (CCR5 chemokine receptor binding) defines the molecular recognition event between ligands and the CCR5 receptor, a process shaped by tyrosine sulfation, membrane cholesterol, and structural features of the binding pocket. Its importance spans HIV-1 pathogenesis, inflammatory disease, and therapeutic development, making it a persistent focus of chemokine receptor research. CRISPR-engineered cell models provide a powerful way to dissect the genetic and biochemical determinants of this binding activity.
References
- 1. Calmet P et al.. 2020. Cholesterol impacts chemokine CCR5 receptor ligand-binding activity.. FEBS J 287(11):2367-2385 PMID: 31738467
- 2. Oppermann M. 2004. Chemokine receptor CCR5: insights into structure, function, and regulation.. Cell Signal 16(11):1201-10 PMID: 15337520
- 3. Rao DA et al.. 2017. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.. Nature 542(7639):110-114 PMID: 28150777
- 4. Arimont M et al.. 2017. Structural Analysis of Chemokine Receptor-Ligand Interactions.. J Med Chem 60(12):4735-4779 PMID: 28165741
- 5. Scurci I et al.. 2021. CCR5 tyrosine sulfation heterogeneity generates cell surface receptor subpopulations with different ligand binding properties.. Biochim Biophys Acta Gen Subj 1865(1):129753 PMID: 32991968
- 6. Zhang H et al.. 2021. Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5.. Nat Commun 12(1):4151 PMID: 34230484
- 7. Kumar A. 2024. CB-0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti-HIV candidate: Computational and in vitro approach.. Biotechnol Appl Biochem 71(4):849-859 PMID: 38556770
- 8. Verhallen L et al.. 2023. "Glyco-sulfo barcodes" regulate chemokine receptor function.. Cell Mol Life Sci 80(2):55 PMID: 36729338
