GO:0031728 CCR3 chemokine receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031728 (CCR3 chemokine receptor binding) is a molecular function describing the binding of a ligand to the CCR3 chemokine receptor.
• The interaction is highly dependent on local pH and ionic strength, which regulate CCR3 function.
• Key ligands include eotaxin (CCL11), CCL8, CCL27, and CCL28, with binding specificity determined by distinct receptor elements.
• CCR3 binding is implicated in allergic inflammation, neointimal lesion formation, and cancer progression.
• Cholesterol binding motifs in CCR3 may modulate its activity and ligand recognition.
• Small molecule antagonists targeting CCR3 binding are explored as therapeutic agents.
Description
GO:0031728, CCR3 chemokine receptor binding, is a molecular function term that describes the binding of a ligand to the CCR3 chemokine receptor. This interaction is central to chemokine signaling, which orchestrates immune cell trafficking and activation. The CCR3 receptor is a G protein-coupled receptor primarily expressed on eosinophils, basophils, and Th2 lymphocytes, and its ligands include eotaxin (CCL11), CCL8, CCL27, and CCL28. The binding event is not merely a passive association; it is highly sensitive to the local environment, with pH and ionic strength profoundly influencing receptor function. Understanding the molecular details of CCR3 binding is therefore critical for deciphering how chemokines selectively activate their receptors and for developing targeted therapies. Researchers study CCR3 chemokine receptor binding to uncover the rules of chemokine receptor activation and selectivity. The binding interface involves specific extracellular loops and N-terminal regions of CCR3, as revealed by chimera complementation and peptide mapping studies. Moreover, cholesterol binding motifs within CCR3 have been identified in silico, suggesting that membrane lipid composition may modulate ligand binding. These findings highlight the complexity of CCR3 interactions and their potential as therapeutic targets in allergic and inflammatory diseases. This article provides a comprehensive overview of GO:0031728, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental approaches. By integrating authoritative QuickGO data with verified PubMed literature, we aim to equip researchers with a clear framework for studying CCR3 chemokine receptor binding and its role in health and disease.
CCR3 chemokine receptor binding At A Glance
| GO ID | GO:0031728 |
|---|---|
| GO term | CCR3 chemokine receptor binding |
| Ontology | molecular_function |
| Synonym | CCR3 chemokine receptor ligand, eosinophil eotaxin receptor binding |
| Major function | Binding to the CCR3 chemokine receptor, initiating signaling cascades |
| Key ligands | Eotaxin (CCL11), CCL8, CCL27, CCL28 |
| Regulatory factors | Local pH, ionic strength, cholesterol binding motifs |
| Associated diseases | Allergic inflammation, neointimal lesions, cancer |
What Is GO:0031728?
CCR3 chemokine receptor binding (GO:0031728) is defined as the binding to a CCR3 chemokine receptor. In other words, it is the molecular function of a ligand physically interacting with the CCR3 receptor protein. This binding event is the first step in CCR3-mediated signaling and is essential for chemokine-induced cellular responses. The term encompasses interactions with natural chemokine ligands such as eotaxin (CCL11), as well as synthetic antagonists or engineered binding proteins.
Why Is CCR3 chemokine receptor binding Important in Cell Biology?
CCR3 chemokine receptor binding is a fundamental molecular event that governs immune cell recruitment and activation. It is the initial step in a signaling cascade that leads to eosinophil chemotaxis, degranulation, and cytokine release, which are critical in allergic inflammation and asthma. Beyond allergy, CCR3 binding has been implicated in pathological vascular remodeling, such as neointimal lesion formation after arterial injury, and in tumor progression. The binding specificity and affinity are finely tuned by the local environment, including pH and ionic strength, which can dramatically alter receptor function. Therefore, understanding CCR3 binding is essential for designing drugs that can selectively block or modulate this interaction for therapeutic benefit.
• Drives eosinophil recruitment in allergic asthma and atopic dermatitis.
• Mediates neointimal hyperplasia in allograft arteries via CCL11/CCR3-PI3K/AKT signaling.
• Involved in cancer progression, including tumor-associated macrophage recruitment.
• Binding affinity is modulated by pH and ionic strength, affecting inflammatory microenvironments.
• Cholesterol binding motifs in CCR3 may influence ligand recognition and receptor stability.
• Small molecule antagonists targeting CCR3 binding are in development for allergic diseases.
• CCR3 binding specificity is determined by distinct extracellular receptor elements.
• CCL8 and other chemokines interact with CCR3, expanding its ligand repertoire.
• CCR3 activation by CCL27/CCL28 reveals rules of chemokine receptor selectivity.
• CCR3 binding is a potential biomarker for eosinophilic disorders and therapeutic monitoring.
Molecular Mechanism of CCR3 chemokine receptor binding
Ligand Recognition and Binding Interface
In simple terms: The CCR3 receptor has specific pockets that recognize and grab onto chemokines like eotaxin.
The binding of chemokines to CCR3 involves multiple extracellular domains, including the N-terminus and extracellular loops. Studies using chimera complementation have identified interacting elements that determine chemokine-binding specificity. Peptides derived from CCR3 can bind eotaxin, confirming that the receptor's extracellular regions are crucial for ligand recognition. The binding interface is not a single site but a composite of several structural elements that together confer high affinity and selectivity.
Role of Local pH and Ionic Strength
In simple terms: The acidity and saltiness around the receptor can change how well it binds to chemokines.
CCR3 function is highly dependent on local pH and ionic strength. At acidic pH, the binding of eotaxin to CCR3 is enhanced, whereas high ionic strength reduces binding. This sensitivity allows CCR3 to respond to the acidic microenvironment of inflamed tissues, where it promotes eosinophil recruitment. The pH-dependent binding is likely due to protonation of key residues in the ligand or receptor, affecting electrostatic interactions.
Cholesterol Binding Motifs and Membrane Modulation
In simple terms: Cholesterol in the cell membrane can interact with CCR3 and influence its activity.
In silico identification of cholesterol binding motifs in CCR3 suggests that membrane cholesterol may directly bind to the receptor and modulate its conformation or ligand binding. Cholesterol-rich microdomains could concentrate CCR3 and its ligands, enhancing signaling efficiency. This adds another layer of regulation to CCR3 chemokine receptor binding, linking lipid metabolism to chemokine signaling.
Ligand Specificity and Receptor Activation
In simple terms: Different chemokines can bind CCR3, but they may trigger different responses.
CCR3 binds multiple chemokines, including eotaxin (CCL11), CCL8, CCL27, and CCL28. The rules of engagement for receptor activation and selectivity by CCL27 and CCL28 have been studied, revealing that subtle differences in ligand structure determine whether binding leads to full activation or antagonism. CCL8 also interacts with CCR3, and its functional expression can influence CCR3-mediated responses. This ligand promiscuity allows CCR3 to integrate diverse inflammatory signals.
Small Molecule Antagonists and Therapeutic Targeting
In simple terms: Drugs can be designed to block CCR3 binding and reduce inflammation.
Small molecule antagonists for CCR3 have been developed to inhibit chemokine binding and downstream signaling. These antagonists typically bind to the receptor's extracellular domains, competing with natural ligands. Understanding the molecular details of CCR3 binding is essential for optimizing antagonist potency and selectivity. Such compounds are promising for treating allergic diseases and other CCR3-mediated pathologies.
Key Genes Involved in GO:0031728 CCR3 chemokine receptor binding
The following genes and proteins are central to CCR3 chemokine receptor binding and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCR3 | Chemokine receptor that binds eotaxin and other ligands | Primary target for knockout and point mutation studies |
| CCL11 | Eotaxin; major ligand for CCR3 | Key agonist in allergic inflammation models |
| CCL8 | Chemokine ligand that interacts with CCR3 | Alternative ligand for studying binding specificity |
| CCL27 | Chemokine ligand for CCR3 and CCR10 | Used to probe receptor selectivity rules |
| CCL28 | Chemokine ligand for CCR3 and CCR10 | Reveals determinants of receptor activation |
| PI3K | Downstream signaling kinase activated by CCR3 | Mediates neointimal lesion formation |
| AKT | Serine/threonine kinase in CCR3 signaling | Effector of CCL11/CCR3 axis in vascular remodeling |
| CD34 | Marker for fibroblast progenitors | Identified in CCL11/CCR3-driven neointima |
| PI16 | Fibroblast progenitor marker | Co-expressed with CD34 in allograft lesions |
| GNAI | G protein alpha subunit coupled to CCR3 | Mediates downstream signaling upon binding |
| ARRB1 | Beta-arrestin 1; regulates CCR3 desensitization | Modulates receptor internalization |
| ARRB2 | Beta-arrestin 2; regulates CCR3 trafficking | Affects signaling duration |
| GRK2 | G protein-coupled receptor kinase 2 | Phosphorylates activated CCR3 |
| GRK3 | G protein-coupled receptor kinase 3 | Phosphorylates activated CCR3 |
| MAPK1 | ERK2; downstream effector of CCR3 | Transduces chemokine signals to nucleus |
| MAPK3 | ERK1; downstream effector of CCR3 | Transduces chemokine signals to nucleus |
| NFKB1 | Transcription factor activated by CCR3 signaling | Drives inflammatory gene expression |
| STAT6 | Transcription factor in Th2 responses | Cooperates with CCR3 signaling in allergy |
How Is CCR3 chemokine receptor binding Regulated?
CCR3 chemokine receptor binding is regulated at multiple levels. Local pH and ionic strength directly modulate the binding affinity of eotaxin to CCR3, with acidic pH enhancing binding and high salt concentrations inhibiting it. Cholesterol binding motifs in CCR3 suggest that membrane lipid composition can influence receptor conformation and ligand accessibility. Additionally, receptor desensitization and internalization are controlled by G protein-coupled receptor kinases (GRKs) and beta-arrestins, which phosphorylate and uncouple the receptor from G proteins after prolonged agonist exposure. These regulatory mechanisms ensure that CCR3 signaling is tightly controlled in time and space.
CCR3 chemokine receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCR3 | Allergic asthma | CCR3 knockout mouse model with ovalbumin challenge |
| CCL11 | Neointimal hyperplasia | Arterial injury model in CCL11 transgenic mice |
| CCR3 | Atopic dermatitis | Skin inflammation model with CCR3 antagonist treatment |
| CCL8 | Inflammatory bowel disease | CCL8 knockout mice with DSS-induced colitis |
| CCR3 | Cancer (e.g., melanoma) | Xenograft model with CCR3-overexpressing tumor cells |
Allergic Inflammation and Asthma
CCR3 chemokine receptor binding is a key driver of eosinophil recruitment in allergic asthma and atopic dermatitis. Eotaxin (CCL11) binding to CCR3 triggers eosinophil chemotaxis and activation, leading to airway inflammation and hyperresponsiveness. Small molecule antagonists that block CCR3 binding are being developed as anti-inflammatory agents. The pH sensitivity of CCR3 binding may exacerbate inflammation in acidic microenvironments of asthmatic airways.
Vascular Remodeling and Neointimal Lesions
The CCL11/CCR3 axis promotes neointimal lesion formation in allograft arteries. CD34+ PI16+ fibroblast progenitors aggravate neointimal lesions via CCL11/CCR3-PI3K/AKT signaling. Blocking CCR3 binding could therefore be a therapeutic strategy to prevent vascular restenosis after transplantation or angioplasty.
Cancer Progression
CCR3 binding is implicated in tumor progression, where chemokine gradients recruit CCR3-expressing cells to the tumor microenvironment. Small molecule antagonists for CCR3 are explored as anticancer agents due to their ability to inhibit tumor-associated macrophage recruitment and angiogenesis. The role of CCR3 in cancer is context-dependent and varies by tumor type.
From CCR3 chemokine receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CCR3 binding mediate eosinophil recruitment? | CCR3 knockout mouse |
| Which residues are critical for eotaxin binding? | Point mutations in CCR3 extracellular loops |
| Can a tagged CCR3 be used for imaging? | Knock-in of fluorescent protein at CCR3 locus |
| Does overexpression of CCR3 enhance signaling? | CCR3 overexpression cell lines |
| What is the role of cholesterol binding motif? | Point mutation of cholesterol-binding residues |
| Can CRISPR screen identify regulators of CCR3 binding? | Genome-wide CRISPR library screening |
How to Study the CCR3 chemokine receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding | Affinity and kinetics of ligand-receptor interaction | Screening antagonists for CCR3 |
| Calcium flux assay | G protein-mediated signaling | Functional activation by CCR3 ligands |
| Chemotaxis assay | Cell migration in response to chemokine | Eosinophil recruitment studies |
| Surface plasmon resonance | Real-time binding kinetics | Measuring affinity of engineered ligands |
| Molecular dynamics simulation | Conformational changes and binding motifs | Predicting cholesterol binding sites |
| Chimera complementation | Identification of interacting receptor elements | Mapping ligand specificity determinants |
| CRISPR knockout screen | Genes required for CCR3 binding | Discovery of novel regulators |
Binding Assays
Radioligand binding assays using iodinated eotaxin and CCR3-expressing membranes are standard for measuring binding affinity and kinetics. These assays can be adapted to test pH and ionic strength effects. Fluorescence polarization and surface plasmon resonance (SPR) provide real-time binding data without radioactivity.
Cell-Based Signaling Assays
Calcium flux assays and cAMP inhibition assays measure CCR3 activation upon ligand binding. Chemotaxis assays using Transwell plates assess functional responses of eosinophils or CCR3-transfected cells. These methods link binding to downstream cellular outcomes.
Structural and Computational Approaches
In silico modeling and molecular dynamics simulations can predict cholesterol binding motifs and ligand-receptor interactions. Chimera complementation studies identify interacting elements by swapping domains between CCR3 and related receptors. These approaches guide mutagenesis experiments.
CRISPR-Based Genetic Screens
Genome-wide CRISPR knockout screens can identify genes that regulate CCR3 expression or binding. For example, screening for loss of eotaxin binding in CCR3-expressing cells can reveal novel modulators. Such screens are powerful for uncovering unknown components of the CCR3 binding pathway.
How CRISPR Can Be Used to Study GO:0031728 CCR3 chemokine receptor binding
Knockout
CRISPR knockout of CCR3 or its ligands (e.g., CCL11) can abolish binding and downstream signaling. CCR3 knockout mice are used to study eosinophil recruitment in asthma models. Knockout of CCL11 reduces neointimal lesion formation in allograft arteries.
Point Mutation
Point mutations in CCR3 extracellular domains can identify residues critical for ligand binding. For example, mutating charged residues in the N-terminus may affect eotaxin binding. Such mutants help dissect the binding interface and pH sensitivity.
Knock-in
Knock-in of a fluorescent tag (e.g., GFP) at the CCR3 locus allows real-time imaging of receptor trafficking and binding in live cells. Tagged CCR3 can be used to study receptor internalization after ligand binding.
Overexpression
Overexpression of CCR3 in cell lines (e.g., HEK293) enhances binding signals for biochemical assays. This approach is useful for screening small molecule antagonists and for structural studies.
How EDITGENE Supports CCR3 chemokine receptor binding Research
Researchers studying CCR3 chemokine receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand recognition, signaling, or disease progression. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this discovery process, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for CCR3 chemokine receptor binding research.
Frequently Asked Questions About CCR3 chemokine receptor binding
What is CCR3 chemokine receptor binding?
CCR3 chemokine receptor binding (GO:0031728) is the molecular function of a ligand physically interacting with the CCR3 receptor, initiating signaling.
What genes are involved in CCR3 chemokine receptor binding?
Key genes include CCR3, CCL11 (eotaxin), CCL8, CCL27, CCL28, and downstream signaling molecules like PI3K and AKT.
How is CCR3 binding regulated?
It is regulated by local pH and ionic strength, cholesterol binding motifs, and receptor desensitization via GRKs and beta-arrestins.
What diseases are associated with CCR3 binding?
Allergic asthma, atopic dermatitis, neointimal hyperplasia, and certain cancers.
What methods are used to study CCR3 binding?
Radioligand binding, calcium flux, chemotaxis, SPR, molecular dynamics, and CRISPR screens.
Can CRISPR be used to study CCR3 binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect CCR3 binding mechanisms.
What is the role of cholesterol in CCR3 binding?
Cholesterol binding motifs in CCR3 may modulate receptor conformation and ligand binding.
How does pH affect CCR3 binding?
Acidic pH enhances eotaxin binding to CCR3, while high ionic strength inhibits it.
What are small molecule antagonists for CCR3?
They are compounds that block CCR3 binding and are developed for allergic diseases.
What is the clinical relevance of CCR3 binding?
It is a therapeutic target for allergic inflammation, vascular remodeling, and cancer.
Conclusion
GO:0031728, CCR3 chemokine receptor binding, is a critical molecular function that initiates immune cell recruitment and activation. Its regulation by pH, ionic strength, and cholesterol highlights the complexity of chemokine signaling. Understanding this binding event offers therapeutic opportunities for allergic diseases, vascular disorders, and cancer. EDITGENE provides advanced CRISPR tools to study CCR3 binding and accelerate drug discovery.
References
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- 3. Ye J et al.. 2000. Characterization of binding between the chemokine eotaxin and peptides derived from the chemokine receptor CCR3.. J Biol Chem 275(35):27250-7 PMID: 10859315
- 4. Xu X et al.. 2025. CD34(+) PI16(+) fibroblast progenitors aggravate neointimal lesions of allograft arteries via CCL11/CCR3-PI3K/AKT pathway.. Theranostics 15(6):2523-2543 PMID: 39990233
- 5. Huang M et al.. 2025. Rules of engagement: Determinants of chemokine receptor activation and selectivity by CCL27 and CCL28.. J Biol Chem 301(11):110736 PMID: 40975172
- 6. Willems LI et al.. 2010. Small molecule antagonists for chemokine CCR3 receptors.. Med Res Rev 30(5):778-817 PMID: 19967721
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- 8. Dairaghi DJ et al.. 1997. Chemokine receptor CCR3 function is highly dependent on local pH and ionic strength.. J Biol Chem 272(45):28206-9 PMID: 9353270
