CCR1

Official Full Name

C-C motif chemokine receptor 1

Organism

Homo sapiens

GeneID

1230

Background

This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. The ligands of this receptor include macrophage inflammatory protein 1 alpha (MIP-1 alpha), regulated on activation normal T expressed and secreted protein (RANTES), monocyte chemoattractant protein 3 (MCP-3), and myeloid progenitor inhibitory factor-1 (MPIF-1). Chemokines and their receptors mediated signal transduction are critical for the recruitment of effector immune cells to the site of inflammation. Knockout studies of the mouse homolog suggested the roles of this gene in host protection from inflammatory response, and susceptibility to virus and parasite. This gene and other chemokine receptor genes, including CCR2, CCRL2, CCR3, CCR5 and CCXCR1, are found to form a gene cluster on chromosome 3p. [provided by RefSeq, Jul 2008]

Synonyms

CKR1; CD191; CKR-1; HM145; CMKBR1; MIP1aR; SCYAR1;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

METPNTTEDYDTTTEFDYGDATPCQKVNERAFGAQLLPPLYSLVFVIGLVGNILVVLVLVQYKRLKNMTSIYLLNLAISDLLFLFTLPFWIDYKLKDDWVFGDAMCKILSGFYYTGLYSEIFFIILLTIDRYLAIVHAVFALRARTVTFGVITSIIIWALAILASMPGLYFSKTQWEFTHHTCSLHFPHESLREWKLFQALKLNLFGLVLPLLVMIICYTGIIKILLRRPNEKKSKAVRLIFVIMIIFFLFWTPYNLTILISVFQDFLFTHECEQSRHLDLAVQVTEVIAYTHCCVNPVIYAFVGERFRKYLRQLFHRRVAVHLVKWLPFLSVDRLERVSSTSPSTGEHELSAGF

Open

Disease

Chronic obstructive pulmonary disease, Diabetes mellitus, Rheumatoid arthritis

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

3 +

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Detailed Information

CCR1 (C-C Motif Chemokine Receptor 1) is located on chromosome 3p21.31 and encodes a typical class A G protein-coupled receptor (GPCR) comprising 355 amino acids with seven transmembrane domains (7TM). The ligand-binding pocket is primarily formed by transmembrane helices 2, 3, and 7 (TM2/3/7), allowing CCR1 to interact with multiple CC chemokines including CCL3, CCL5, CCL7, and CCL15. In 2022, cryo-electron microscopy revealed the 3D structure of CCR1 in complex with its ligand CCL15: the full-length isoform (CCL15L) preferentially activates Gαi signaling, whereas the truncated form (CCL15S), generated by metalloprotease cleavage, selectively triggers β-arrestin-mediated pathways. This biased signaling is governed by a conserved amino acid residue at the base of TM7 (Arg²⁶⁰), which acts as a “molecular toggle” to determine downstream signaling directionality.

Figure 1. Molecular role of CCR1 in intracranial aneurysm, subarachnoid hemorrhage, and intracranial hemorrhage, with CCR1 inhibition effectively attenuating neuroinflammation and blood-brain barrier damage. (Tian Q, et al., 2024)

Biological Functions and Disease Associations

CCR1 is highly expressed on monocytes, neutrophils, and dendritic cells. Upon ligand binding, it triggers intracellular calcium influx and cytoskeletal rearrangement, facilitating immune cell migration toward inflammatory sites. Key roles include:

Asthma Pathogenesis: The CCL15–CCR1 axis initiates early inflammatory cascades in asthma. Eosinophils migrate into the airway via CCR1 and release IL-5 and TGF-β, driving airway hyperresponsiveness and mucus hypersecretion. CCR1 knockout models demonstrate >70% reduction in pulmonary inflammatory cell infiltration, underscoring its essential role.
Autoimmunity and Fibrosis: In thyroid-associated ophthalmopathy (TAO), CCR1 expression is significantly upregulated in orbital fibroblasts (P < 0.05), promoting fibroblast proliferation and glycosaminoglycan (GAG) synthesis in response to CCL3 and CCL5. This contributes to extraocular muscle hypertrophy and orbital fibrosis. In rheumatoid arthritis, CCR1⁺ macrophage infiltration correlates with severity of bone erosion.
Infection and Neuroinflammation: CCR1 acts as a co-receptor for HIV-1, facilitating viral entry into macrophages alongside CD4. In Alzheimer’s disease models, the CCL5–CCR1 axis activates ERK1/2 signaling in microglia, promoting neuroinflammation and amyloid-β deposition.

Clinical Translation and Therapeutic Progress

Structure-based drug development targeting CCR1 has made notable advances:

Biased Ligand Design: Leveraging cryo-EM structures (resolution 3.1 Å), researchers engineered CCL15 variants that selectively activate G protein signaling while suppressing β-arrestin recruitment. These biased agonists reduce airway remodeling in murine asthma models without inducing broad immunosuppression.
Small Molecule Antagonists: Compounds such as BX471 (Phase III, failed) and CCX354 (Phase II) inhibit CCL3 binding to CCR1 but showed limited clinical efficacy. Next-generation allosteric inhibitors stabilize the receptor’s inactive conformation, exhibiting improved selectivity and reducing GAG synthesis by 40% in TAO patients.
Combination Therapies: In giant cell tumor of bone (GCTB), CCR1 antagonists combined with the RANKL-blocking antibody denosumab synergistically inhibit osteoclastogenesis and reduce tumor recurrence rates.

Challenges and Evolutionary Insights

The primary challenge in CCR1-targeted therapy lies in ligand redundancy—multiple chemokines (e.g., CCL3, CCL5, CCL7, CCL15) activate CCR1, making single-ligand blockade insufficient. Emerging strategies to address this include:

Bispecific antibodies targeting multiple ligands,
Downstream inhibition of shared signaling nodes.

Furthermore, the Arg²⁶⁰ residue, highly conserved in ~90% of class A GPCRs, presents a novel opportunity for broader drug design. Allosteric modulators targeting this conserved site may extend beyond CCR1 to therapeutically relevant GPCRs such as opioid receptors (for analgesia) and angiotensin receptors (for hypertension).

Reference

Cheng JF, Jack R. CCR1 antagonists. Mol Divers. 2008 Feb;12(1):17-23.
Tian Q, Yan Z, Guo Y, et al. Inflammatory Role of CCR1 in the Central Nervous System. Neuroimmunomodulation. 2024;31(1):173-182.

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