GO:0031726 CCR1 chemokine receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031726 (CCR1 chemokine receptor binding) is a molecular function describing the binding of a ligand to the CCR1 chemokine receptor, a class A G protein-coupled receptor.
• CCR1 binds multiple chemokines, including CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), and CCL23, and also binds small-molecule antagonists such as BX 471.
• Ligand binding to CCR1 follows a two-site, two-step model in which the chemokine N-terminus first docks at the receptor N-terminal domain and then inserts into the transmembrane pocket to activate G protein signaling.
• CCR1 can be constitutively active and can signal through both G protein-dependent and beta-arrestin-dependent pathways, which affects internalization and downstream responses.
• CCR1 binding is implicated in inflammatory diseases, including septic acute lung injury, respiratory syncytial virus infection, and cancer, making it a therapeutic target.
• Research on CCR1 binding uses binding assays, structural biology, CRISPR knockout, and knock-in models to dissect ligand-receptor interactions and signaling.
Description
GO:0031726, CCR1 chemokine receptor binding, is a molecular function term that describes the binding of a ligand to the CCR1 chemokine receptor. CCR1 is a class A G protein-coupled receptor (GPCR) that recognizes inflammatory chemokines such as CCL3, CCL5, CCL7, and CCL23. This binding event is the first step in a signaling cascade that controls immune cell migration, activation, and cytokine release, and it is therefore central to both normal immune surveillance and pathological inflammation. Understanding the molecular details of CCR1 binding is important for drug discovery, because small molecules and antibodies that block or modulate this interaction can alter disease outcomes in inflammatory and infectious conditions. The term is also relevant to cancer biology, where CCR1-mediated signaling can promote tumor-associated macrophage recruitment and tumor progression. Researchers studying CCR1 binding use a combination of biochemical binding assays, structural biology, and CRISPR-based genetic models to define how ligands engage the receptor and how this engagement translates into cellular responses.
CCR1 chemokine receptor binding At A Glance
| GO ID | GO:0031726 |
|---|---|
| GO term | CCR1 chemokine receptor binding |
| Ontology | molecular_function |
| Synonym | CCR1 chemokine receptor ligand; macrophage inflammatory protein-1 alpha receptor binding |
| Major function | Binding of chemokines and small-molecule ligands to the CCR1 receptor, initiating or modulating downstream signaling |
| Receptor family | Class A G protein-coupled receptor (chemokine receptor) |
| Key ligands | CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL23, and synthetic antagonists such as BX 471 |
| Signaling pathways | G protein-dependent (G alpha i) and beta-arrestin-dependent pathways |
| Disease relevance | Inflammation, septic acute lung injury, respiratory syncytial virus infection, cancer |
What Is GO:0031726?
CCR1 chemokine receptor binding (GO:0031726) is defined as the binding of a molecule to a CCR1 chemokine receptor. In practice, this includes the binding of natural chemokine ligands, such as CCL3, CCL5, CCL7, and CCL23, as well as synthetic antagonists and biased ligands that target the receptor. The term is a molecular function annotation that captures the physical interaction between a ligand and CCR1, independent of whether that interaction leads to full activation, partial activation, or inhibition. Because CCR1 is a GPCR, ligand binding typically occurs in two steps: initial docking at the receptor N-terminal domain, followed by insertion of the ligand N-terminus into the transmembrane binding pocket, which triggers conformational changes and G protein activation. This definition is based on the QuickGO entry for GO:0031726 and is supported by experimental studies of CCR1-ligand interactions.
Why Is CCR1 chemokine receptor binding Important in Cell Biology?
CCR1 chemokine receptor binding is important because it is the initiating event for a broad range of immune and inflammatory responses. Ligand binding to CCR1 activates intracellular signaling that drives chemotaxis, cytokine production, and immune cell polarization, and dysregulation of this process contributes to diseases such as septic acute lung injury, viral infections, and cancer. Because CCR1 is a druggable GPCR, understanding its binding mechanism supports the development of antagonists and biased ligands that can selectively modulate inflammation without fully blocking protective immune functions. In addition, CCR1 binding is a model system for studying the two-site, two-step mechanism of chemokine receptor activation, which is broadly relevant to other GPCRs.
• CCR1 binding initiates G protein-mediated signaling that controls immune cell migration and activation.
• CCR1 is a therapeutic target in inflammatory diseases, including septic acute lung injury and respiratory syncytial virus infection.
• Small-molecule antagonists such as BX 471 bind CCR1 and can block its activity, making CCR1 binding a key drug discovery focus.
• Biased ligands that preferentially activate G protein or beta-arrestin pathways can be designed based on CCR1 binding mechanisms.
• CCR1 is constitutively active in some contexts, and ligand binding can modulate both G protein-dependent and independent internalization.
• CCR1 binding is studied using structural biology, which reveals how chemokines dock and activate the receptor.
• CRISPR knockout and knock-in models allow researchers to test the causal role of CCR1 and its ligands in disease.
• CCR1 binding is relevant to cancer biology, where it can promote macrophage polarization and tumor progression.
• Understanding CCR1 binding helps explain why different chemokines can produce distinct signaling outcomes.
• CCR1 binding assays are used to screen for new antagonists and to measure ligand affinity and selectivity.
Molecular Mechanism of CCR1 chemokine receptor binding
Two-site, two-step binding model
In simple terms: The ligand first grabs the outside of the receptor, then inserts into a pocket to turn it on.
CCR1 binding follows a two-site, two-step model. In the first step, the chemokine ligand docks onto the N-terminal domain and extracellular loops of CCR1 through electrostatic interactions. In the second step, the N-terminus of the chemokine inserts into the transmembrane binding pocket, triggering conformational changes that lead to G protein activation. This model has been validated for CCR1 using mutagenesis and binding experiments, and it explains how different chemokines can have different potencies.
Ligand recognition and selectivity
In simple terms: Different chemokines can bind CCR1, but they do not all trigger the same response.
CCR1 recognizes multiple chemokines, including CCL3, CCL5, CCL7, and CCL23, as well as synthetic ligands such as BX 471. The receptor's N-terminal domain and extracellular loops determine ligand selectivity, while the transmembrane pocket controls efficacy. Structural studies of chemokine receptors have revealed that subtle differences in ligand-receptor contacts can bias signaling toward G protein or beta-arrestin pathways. This selectivity is important for designing drugs that block only pathogenic signaling.
G protein activation and downstream signaling
In simple terms: Once the ligand binds, the receptor activates G proteins that send signals inside the cell.
Ligand binding to CCR1 promotes the exchange of GDP for GTP on G alpha i subunits, leading to inhibition of adenylyl cyclase and activation of downstream effectors such as PI3K and MAPK. CCR1 can also signal through beta-arrestin, which mediates receptor internalization and additional signaling events. The balance between G protein and beta-arrestin signaling depends on the ligand and the cellular context, and this balance can be exploited for therapeutic benefit.
Constitutive activity and internalization
In simple terms: CCR1 can be active even without a ligand, and it can be pulled inside the cell after activation.
CCR1 exhibits constitutive activity, meaning it can signal in the absence of ligand. This constitutive activity leads to G protein-independent, beta-arrestin-mediated internalization, which regulates receptor levels on the cell surface. Ligand binding can further modulate internalization and recycling, and this process is important for controlling the duration and strength of CCR1 signaling. Understanding constitutive activity is critical for interpreting knockout and overexpression experiments.
Allosteric modulation and biased ligands
In simple terms: Some drugs bind CCR1 at a different site and change how it responds to chemokines.
CCR1 contains an intracellular allosteric binding site that can be targeted by small molecules such as fluorophore-labeled pyrrolones. Biased ligands can preferentially activate G protein or beta-arrestin pathways, and these ligands have been identified for CCR1. Allosteric modulators and biased ligands offer ways to fine-tune CCR1 signaling for therapeutic purposes, and their development relies on detailed understanding of the binding mechanism.
Key Genes Involved in GO:0031726 CCR1 chemokine receptor binding
The following genes and proteins are central to CCR1 chemokine receptor binding and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCR1 | Receptor that binds chemokines and initiates signaling | Primary target for knockout, knock-in, and binding studies |
| CCL3 | Chemokine ligand (MIP-1alpha) that binds CCR1 | Used in binding assays and inflammation models |
| CCL5 | Chemokine ligand (RANTES) that binds CCR1 | Studied for its role in immune cell recruitment |
| CCL7 | Chemokine ligand (MCP-3) that binds CCR1 | Implicated in septic acute lung injury via CCR1 |
| CCL23 | Chemokine ligand that binds CCR1 | Used to study ligand selectivity and signaling |
| GNAI1 | G alpha i subunit activated by CCR1 | Key mediator of CCR1 signaling |
| ARRB1 | Beta-arrestin 1 involved in CCR1 internalization | Regulates receptor desensitization |
| ARRB2 | Beta-arrestin 2 involved in CCR1 internalization | Regulates receptor desensitization |
| STAT1 | Transcription factor activated downstream of CCR1 | Mediates macrophage polarization in lung injury |
| PIK3CA | PI3K subunit in CCR1 signaling | Downstream effector of G protein signaling |
| MAPK1 | MAP kinase downstream of CCR1 | Mediates inflammatory gene expression |
| MAPK3 | MAP kinase downstream of CCR1 | Mediates inflammatory gene expression |
| CXCL10 | Chemokine that can be modulated by CCR1 signaling | Used as a readout in infection models |
| IL6 | Cytokine induced by CCR1 activation | Marker of inflammation in CCR1 studies |
| TNF | Cytokine induced by CCR1 activation | Marker of inflammation in CCR1 studies |
| CCL2 | Chemokine involved in macrophage recruitment | Studied alongside CCR1 in inflammation |
| NFKB1 | Transcription factor downstream of CCR1 | Regulates inflammatory gene expression |
How Is CCR1 chemokine receptor binding Regulated?
CCR1 chemokine receptor binding is regulated at multiple levels. Ligand availability, receptor expression, and post-translational modifications influence binding. Constitutive activity and beta-arrestin-mediated internalization control the number of receptors on the cell surface. Biased ligands can shift signaling toward G protein or beta-arrestin pathways, effectively regulating the functional outcome of binding. In addition, allosteric modulators can bind to intracellular sites on CCR1 and change its affinity for chemokines. Downstream signaling pathways, including STAT1 and MAPK, can feed back to regulate receptor expression and ligand production, creating complex feedback loops in inflammatory conditions.
CCR1 chemokine receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCR1 | Septic acute lung injury | CCR1 knockout mice or CRISPR knockout cell lines |
| CCL7 | Septic acute lung injury | CCL7 overexpression or knockout in endothelial cells |
| CCR1 | Respiratory syncytial virus infection | CCR1 knockout or agonist-treated airway epithelial cells |
| CCR1 | Cancer / tumor microenvironment | CCR1 knockout in macrophages or tumor cells |
| CCR1 | Inflammatory diseases | CCR1 knock-in reporter cells for binding assays |
Septic acute lung injury
Endothelial-derived CCL7 promotes macrophage polarization and aggravates septic acute lung injury via CCR1-mediated STAT1 succinylation. This study demonstrates that CCR1 binding of CCL7 activates STAT1 and drives inflammatory macrophage polarization, suggesting that blocking CCR1 binding could be a therapeutic strategy for acute lung injury.
Respiratory syncytial virus infection
Activation of CCR1 and preferential recruitment of G alpha i suppress respiratory syncytial virus (RSV) replication, indicating that CCR1 binding can have antiviral effects. This finding suggests that CCR1 agonists or biased ligands might be developed as novel RSV treatment strategies.
Cancer and tumor microenvironment
CCR1-mediated signaling promotes macrophage polarization and can contribute to tumor progression by shaping the tumor microenvironment. Targeting CCR1 binding may reduce tumor-associated macrophage recruitment and improve responses to immunotherapy, although further studies are needed.
Inflammatory and autoimmune diseases
CCR1 binds multiple inflammatory chemokines, and dysregulated CCR1 binding is implicated in chronic inflammatory conditions. Small-molecule antagonists such as BX 471 have been developed to block CCR1 binding and are being explored for inflammatory diseases.
From CCR1 chemokine receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CCR1 binding mediate inflammatory macrophage polarization? | CCR1 knockout macrophages treated with CCL7 |
| Which residues in CCR1 are required for ligand binding? | Point-mutation knock-in of CCR1 in cell lines |
| How does CCR1 constitutive activity affect internalization? | CCR1 overexpression and beta-arrestin knockout cells |
| Can biased ligands selectively activate G protein signaling? | CCR1 knock-in cells with G protein or beta-arrestin reporters |
| What is the role of CCR1 in RSV replication? | CCR1 knockout airway epithelial cells |
| How does CCL7-CCR1 binding affect STAT1 signaling? | STAT1 knockout or knock-in macrophages |
How to Study the CCR1 chemokine receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding | Ligand affinity and receptor density | Screening CCR1 antagonists |
| Cryo-EM | Receptor structure and ligand pose | Understanding binding mechanism |
| CRISPR knockout | Loss of CCR1 function | Testing causal role in inflammation |
| BRET beta-arrestin assay | Beta-arrestin recruitment | Measuring biased signaling |
| cAMP inhibition assay | G alpha i activation | Measuring G protein signaling |
| Calcium flux | Intracellular calcium release | Detecting CCR1 activation |
| Flow cytometry | Cell surface CCR1 expression | Measuring internalization |
| ELISA | Cytokine production | Readout of CCR1-mediated inflammation |
Binding assays
Radioligand binding and fluorescence-based assays are used to measure the affinity and kinetics of ligand binding to CCR1. These assays can be performed with cell membranes expressing recombinant CCR1 or with intact cells, and they are essential for screening antagonists and biased ligands.
Structural biology
X-ray crystallography and cryo-electron microscopy have been used to determine the structure of CCR1 and other chemokine receptors, revealing the two-site binding mechanism and the conformational changes that occur upon ligand binding. These structures guide the design of small-molecule modulators.
CRISPR knockout and knock-in
CRISPR-Cas9 knockout of CCR1 or its ligands, as well as knock-in of point mutations, allows researchers to test the causal role of specific residues in binding and signaling. These models are used in combination with binding assays and signaling readouts.
Signaling assays
G protein activation can be measured using GTPgammaS binding, cAMP inhibition, or calcium flux assays, while beta-arrestin recruitment can be measured using BRET or beta-arrestin complementation assays. These methods define how binding translates into functional outcomes.
How CRISPR Can Be Used to Study GO:0031726 CCR1 chemokine receptor binding
Knockout
CRISPR knockout of CCR1 is used to eliminate receptor expression and test whether a ligand's effects are CCR1-dependent. For example, CCR1 knockout macrophages show reduced STAT1 activation and inflammatory polarization in response to CCL7. Knockout of CCR1 in airway epithelial cells can also reveal its role in RSV replication.
Point Mutation
Point mutations in CCR1 can be introduced by CRISPR knock-in to map the residues required for ligand binding and G protein activation. Mutations in the N-terminal domain or transmembrane pocket can abolish chemokine binding or bias signaling, as shown in two-site model studies.
Knock-in
Knock-in of tagged or reporter CCR1 allows real-time tracking of receptor localization and internalization. Tagged CCR1 can be used in binding assays and imaging experiments to study constitutive internalization and beta-arrestin recruitment.
Overexpression
Overexpression of CCR1 in cell lines is used to amplify binding signals for biochemical assays and to study constitutive activity. Overexpression systems are valuable for screening small-molecule antagonists and biased ligands.
How EDITGENE Supports CCR1 chemokine receptor binding Research
Researchers studying CCR1 chemokine receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand binding, signaling, or disease progression. EDITGENE provides CRISPR-based cell models and screening services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for CCR1 chemokine receptor binding research.
Frequently Asked Questions About CCR1 chemokine receptor binding
What is GO:0031726?
GO:0031726 is the Gene Ontology molecular function term for CCR1 chemokine receptor binding, which describes the binding of a ligand to the CCR1 receptor.
What genes are involved in CCR1 chemokine receptor binding?
Key genes include CCR1 itself, its ligands CCL3, CCL5, CCL7, and CCL23, and signaling mediators such as GNAI1, ARRB1, ARRB2, and STAT1.
What is the function of CCR1?
CCR1 is a G protein-coupled receptor that binds inflammatory chemokines and activates signaling pathways controlling immune cell migration and activation.
How does CCR1 bind its ligands?
CCR1 binding follows a two-site, two-step model: the ligand first docks at the receptor N-terminus, then inserts into the transmembrane pocket to activate G proteins.
What diseases are associated with CCR1 binding?
CCR1 binding is implicated in septic acute lung injury, respiratory syncytial virus infection, cancer, and chronic inflammatory diseases.
What are the synonyms for GO:0031726?
Synonyms include CCR1 chemokine receptor ligand and macrophage inflammatory protein-1 alpha receptor binding.
Which chemokines bind CCR1?
CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), and CCL23 are known to bind CCR1.
How can I study CCR1 binding in the lab?
Common methods include radioligand binding assays, cryo-EM, CRISPR knockout, and beta-arrestin recruitment assays.
Is CCR1 constitutively active?
Yes, CCR1 exhibits constitutive activity that leads to G protein-independent, beta-arrestin-mediated internalization.
What CRISPR models are available for CCR1 research?
CRISPR knockout, point-mutation knock-in, tagged knock-in, and overexpression models are available for CCR1 and its ligands.
Conclusion
GO:0031726, CCR1 chemokine receptor binding, is a central molecular function in inflammatory signaling and immune regulation. The two-site, two-step binding mechanism, the diversity of chemokine ligands, and the balance between G protein and beta-arrestin signaling make CCR1 a rich subject for both basic and translational research. Dysregulated CCR1 binding contributes to diseases such as septic acute lung injury, RSV infection, and cancer, and targeting this interaction with antagonists or biased ligands holds therapeutic promise. CRISPR-based models and binding assays continue to refine our understanding of CCR1 biology and support drug discovery efforts.
References
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- 2. Toy L et al.. 2024. Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1.. ACS Pharmacol Transl Sci 7(7):2080-2092 PMID: 39022357
- 3. Li J et al.. 2022. Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies.. J Virol 96(22):e0130922 PMID: 36317881
- 4. Shao Z et al.. 2022. Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.. Nat Chem Biol 18(3):264-271 PMID: 34949837
- 5. Sanchez J et al.. 2019. Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1.. J Biol Chem 294(10):3464-3475 PMID: 30567735
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