Affinage

CCR5

C-C chemokine receptor type 5 · UniProt P51681

Round 2 corrected
Length
352 aa
Mass
40.5 kDa
Annotated
2026-04-28
130 papers in source corpus 41 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCR5 is a Gi-coupled seven-transmembrane chemokine receptor that transduces signals from CC-chemokines (CCL3, CCL4, CCL5) and serves as the principal coreceptor for macrophage-tropic HIV-1 entry. Agonist binding triggers Giα2-mediated inhibition of adenylyl cyclase, assembly of a RAFTK/Pyk2–Syk–SHP1/2–Grb2 signaling complex, and GRK-dependent C-terminal phosphorylation at a conserved pXpp motif that recruits arrestin-2 for clathrin- and caveolae-mediated internalization followed by actin/RhoGTPase-dependent recycling through early endosomes (PMID:9736452, PMID:10747947, PMID:37244255, PMID:11806977, PMID:14717692). HIV-1 gp120, after CD4-induced conformational change, engages a bipartite site involving the sulfated N-terminal tyrosines and the second extracellular loop of CCR5, exploiting conformational states distinct from those preferentially bound by native chemokines; the 2.7 Å crystal structure shows that maraviroc occupies an allosteric pocket within the transmembrane bundle separate from chemokine and gp120 recognition sites, while homodimerization via TM5 is required for plasma-membrane targeting (PMID:10089882, PMID:9632396, PMID:24030490, PMID:29739880, PMID:23696662). Beyond its immune-cell chemotactic role and HIV-1 coreceptor function — abrogated by the CCR5Δ32 loss-of-function allele (PMID:8756719) — CCR5 acts as a receptor for S. aureus LukED leukotoxin (PMID:23235831), promotes hepatic stellate cell migration via PI3K (PMID:19603542), enables DNA-PKcs-dependent DNA damage repair in glioblastoma (PMID:34239070), and activates neuronal mTORC1 to suppress autophagy and impair clearance of aggregate-prone proteins (PMID:37105172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    Identification of CCR5 as both a CC-chemokine receptor and the essential coreceptor for macrophage-tropic HIV-1 entry resolved the long-standing question of what host factor — beyond CD4 — permitted HIV-1 fusion, and the simultaneous discovery of the CCR5Δ32 loss-of-function allele conferring HIV-1 resistance validated the coreceptor's non-redundant role in vivo.

    Evidence Recombinant CCR5 expression in non-human CD4+ cells reconstituted HIV-1 fusion; molecular cloning with radioligand binding and inositol phosphate assays confirmed chemokine receptor function; genotyping of exposed-uninfected individuals identified CCR5Δ32 homozygosity

    PMID:8639485 PMID:8649511 PMID:8649512 PMID:8658171 PMID:8663314 PMID:8674119 PMID:8751444 PMID:8756719

    Open questions at the time
    • Structural basis of the CD4-gp120-CCR5 ternary complex was unknown
    • Downstream signaling pathways activated by chemokine binding were uncharacterized
    • Mechanism of CCR5 trafficking and desensitization was not addressed
  2. 1998 High

    Defining CCR5's G-protein coupling specificity and endocytic regulation established that the receptor signals through Giα2 in a pertussis-toxin-sensitive manner and internalizes via agonist-dependent (but not PKC-dependent) pathways, distinguishing its regulation from the related coreceptor CXCR4.

    Evidence GTPγS binding, adenylyl cyclase inhibition, and pertussis toxin sensitivity assays with Giα2 co-expression; RANTES-induced internalization with pharmacological dissection comparing CCR5 and CXCR4

    PMID:9718374 PMID:9736452

    Open questions at the time
    • The specific C-terminal phosphorylation sites driving arrestin recruitment were undefined
    • Clathrin vs. caveolae contribution to internalization was not resolved
    • Downstream kinase cascades beyond Gi coupling were unknown
  3. 1999 High

    Demonstration that N-terminal tyrosine sulfation is required for high-affinity binding of both chemokines and the gp120/CD4 complex identified a critical post-translational determinant of CCR5 ligand recognition, while evidence for constitutive CD4-CCR5 association suggested preformed complexes at the cell surface.

    Evidence Tyrosine-to-phenylalanine mutagenesis and sulfation inhibition with binding and HIV-1 infection assays; co-immunoprecipitation of CD4 and CCR5 with antibody competition

    PMID:10089882 PMID:10377443

    Open questions at the time
    • Whether the CD4-CCR5 pre-association is functionally required for HIV entry was debated
    • The stoichiometry of sulfated tyrosine contributions was not resolved
    • Structural details of the sulfated N-terminus engaging gp120 were lacking
  4. 2000 Medium

    Discovery that CCR5 dimerization blocks HIV-1 infection and that chemokine stimulation assembles a RAFTK/Pyk2–Syk–SHP1/2–Grb2 signaling complex revealed both a quaternary-structure-based antiviral mechanism and the intracellular kinase/phosphatase network mediating chemotaxis downstream of CCR5.

    Evidence Anti-CCR5 mAb inducing dimerization blocked HIV-1 replication in PBMCs and SCID mice; co-IP of signaling complex components with dominant-negative RAFTK epistasis and chemotaxis readout

    PMID:10725362 PMID:10747947

    Open questions at the time
    • Dimerization interface residues were not mapped
    • Whether RAFTK-Syk axis operates in all CCR5-expressing cell types was untested
    • Relationship between dimerization and G-protein coupling was unknown
  5. 2002 High

    Pharmacological dissection showed that CCR5 internalizes through both clathrin-coated pits (with arrestin-2 redistribution) and caveolae, and recycles through early endosomes independently of the Golgi, establishing dual endocytic pathways and a rapid recycling itinerary.

    Evidence Sucrose (clathrin inhibitor), nystatin/filipin (caveolae inhibitors), GFP-arrestin-2 imaging, and vesicle transport inhibitors in flow-cytometry-based internalization/recycling assays

    PMID:11806977

    Open questions at the time
    • Relative quantitative contribution of clathrin vs. caveolae pathways was not determined
    • Sorting signals on CCR5 directing each pathway were not identified
    • Whether the two pathways lead to different signaling outcomes was unknown
  6. 2004 High

    Identification that actin polymerization and RhoGTPase activation are required for both CCR5 internalization and recycling, combined with mapping of the small-molecule inhibitor binding pocket at the TM/extracellular-loop interface, connected cytoskeletal dynamics to receptor trafficking and defined pharmacologically targetable receptor architecture.

    Evidence Cytochalasin D, Toxin B, and C3 exoenzyme blocked internalization and recycling; site-directed mutagenesis of CCR5 with saturation binding and HIV-1 infection assays mapped inhibitor-binding residues

    PMID:14717692 PMID:16476734

    Open questions at the time
    • RhoGTPase family member specificity was not resolved
    • Structure of the inhibitor-bound receptor at atomic resolution was not yet available
    • How actin-dependent trafficking feeds back to signaling was unexplored
  7. 2012 High

    Identification of CCR5 as the direct receptor for S. aureus leukotoxin LukED expanded CCR5's biological role beyond chemokine sensing and HIV-1 entry to bacterial pathogenesis, demonstrating that CCR5 deficiency protects against lethal staphylococcal infection.

    Evidence SPR direct binding; cytotoxicity in CCR5+ vs. CCR5-deficient cells; maraviroc blockade; CCR5 knockout mouse S. aureus infection model

    PMID:23235831

    Open questions at the time
    • Structural basis of LukED recognition of CCR5 vs. chemokine recognition was unknown
    • Whether LukED triggers CCR5 signaling before pore formation was not addressed
    • Relevance to human staphylococcal disease outcomes was not established
  8. 2013 High

    The 2.7 Å crystal structure of CCR5 bound to maraviroc revealed that allosteric inhibitors occupy a pocket within the transmembrane bundle distinct from chemokine and gp120 binding sites, while pharmacological studies showed that HIV-1 gp120 exploits low-chemokine-affinity CCR5 conformations, explaining the limited antiviral efficacy of native chemokines.

    Evidence X-ray crystallography at 2.7 Å resolution; radioligand binding with GTP analogs and G-protein-uncoupled CCR5 mutants; HIV-1 infection assays

    PMID:23696662 PMID:24030490

    Open questions at the time
    • Structure of CCR5 in complex with a chemokine or gp120 was not determined
    • Active-state receptor structure with G protein was unavailable
    • Dynamics of conformational switching between states in live cells were unresolved
  9. 2014 High

    Discovery that microRNAs stimulate programmed −1 ribosomal frameshifting on CCR5 mRNA via an RNA pseudoknot, directing the transcript to nonsense-mediated decay, uncovered a novel post-transcriptional mechanism controlling CCR5 protein levels.

    Evidence Reporter assays for −1 PRF; pseudoknot mutagenesis; miRNA transfection; NMD pathway inhibition and mRNA stability measurements

    PMID:25043019

    Open questions at the time
    • Identity and regulation of the specific miRNAs in physiological contexts were incompletely defined
    • Whether −1 PRF-NMD regulation operates in all CCR5-expressing cell types was untested
    • Interplay between this mechanism and lncRNA CCR5AS-mediated stabilization was unknown
  10. 2018 High

    Biophysical characterization established that CCR5 homodimerizes via TM5 in three conformational states, with dimerization required for plasma-membrane targeting; this resolved the structural basis of earlier observations that dimerization modulates both HIV-1 entry and signaling.

    Evidence Cross-linking, BRET/FRET, computational docking, and functional membrane export assays; maraviroc stabilized a distinct dimeric state

    PMID:29739880

    Open questions at the time
    • How dimerization state switches in response to different ligands in real time was not captured
    • Whether TM5 dimerization interface is the sole interface in vivo was not fully resolved
    • Impact of dimerization on arrestin recruitment and G-protein selectivity was not tested
  11. 2019 Medium

    Identification of the antisense lncRNA CCR5AS as a stabilizer of CCR5 mRNA — by blocking Raly-mediated degradation — added a second post-transcriptional layer of CCR5 regulation and linked the SNP rs1015164 to HIV susceptibility via ATF1-dependent CCR5AS transcription.

    Evidence CCR5AS knockdown/overexpression; RNA-IP for Raly-CCR5 mRNA interaction; CCR5 surface expression by flow cytometry; HIV infection assay in CD4+ T cells

    PMID:31209403

    Open questions at the time
    • Whether CCR5AS regulation operates in non-lymphoid CCR5-expressing cells was untested
    • Interplay between CCR5AS and the −1 PRF/NMD pathway was unexplored
    • Whether Raly binding is the sole mechanism of CCR5AS action was not determined
  12. 2023 High

    Structural identification of a conserved pXpp C-terminal phosphorylation motif essential for arrestin-2 recruitment, combined with functional studies in neurons showing CCR5-mediated mTORC1 activation suppresses autophagy and impairs aggregate-prone protein clearance, expanded the mechanistic understanding of CCR5 desensitization and revealed a pathogenic role in neurodegeneration.

    Evidence Crystal structures of arrestin-2–CCR5 phosphopeptide complexes with NMR and phosphosite mutagenesis; conditioned-medium transfer from microglia to neurons with CCR5 KO and maraviroc in HD and tauopathy mouse models

    PMID:37105172 PMID:37244255

    Open questions at the time
    • Full-length CCR5–arrestin-2 complex structure is not available
    • Whether mTORC1 activation is mediated through Gi or arrestin-biased signaling is unresolved
    • Clinical relevance of CCR5 antagonism in human neurodegenerative disease is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of CCR5 in complex with a native chemokine or gp120/CD4, the full signaling wiring diagram distinguishing G-protein-dependent from arrestin-biased pathways across different cell types, and whether the multiple post-transcriptional regulatory mechanisms (−1 PRF/NMD, lncRNA CCR5AS) are coordinated or independent.
  • No structure of agonist-bound or G-protein-coupled CCR5 is available
  • Cell-type-specific signaling bias between Gi and arrestin pathways is undefined
  • Coordination between −1 PRF/NMD and CCR5AS post-transcriptional mechanisms is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0120274 virus coreceptor activity 5 GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 7 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
ARRB1CD4CXCR4GRB2PTPN11PTPN6PYK2SYK
Complex memberships
CCR5 homodimerCCR5–CXCR4 heterodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CCR5 (CC CKR5) was identified as a fusion cofactor (co-receptor) for macrophage-tropic HIV-1 entry, acting as a G protein-coupled receptor for RANTES, MIP-1alpha, and MIP-1beta; recombinant CCR5 rendered CD4-expressing nonhuman cells fusion-competent with macrophage-tropic HIV-1 envelopes. Cell fusion assay; recombinant receptor expression in nonhuman cells; mRNA detection Science High 8649511 8649512 8658171 8674119 8751444
1996 A 32-bp deletion in CCR5 (CCR5Δ32) causes a frameshift producing a truncated, non-functional protein that is not transported to the cell surface; homozygosity for this allele confers strong resistance to HIV-1 infection by macrophage-tropic strains. Genetic sequencing; cell-surface expression assay; in vitro HIV infection assay of primary CD4+ T cells from homozygous individuals Cell / Nature High 8751444 8756719
1996 CCR5 was molecularly cloned and functionally characterized as a GPCR that binds RANTES, MIP-1beta, and MIP-1alpha with high affinity and generates inositol phosphates in response to these chemokines; it is expressed in lymphoid organs, peripheral blood leukocytes, macrophages, and T cells. Molecular cloning; radioligand binding assays; inositol phosphate signaling assay in transfected cells; Northern blot expression analysis The Journal of Biological Chemistry High 8639485 8663314
1996 CD4 binding to gp120 dramatically enhances the affinity of gp120 for CCR5; the gp120-CD4 complex specifically binds CCR5 and inhibits binding of natural CCR5 ligands MIP-1alpha and MIP-1beta; the V3 loop of gp120 is required for this interaction. Competitive binding assay (125I-MIP-1beta displacement); cell-based fusion assay; gp120 mutagenesis Nature High 8906795 8906796
1998 A conserved gp120 structure adjacent to the V3 loop (CD4-induced epitope region) is critical for CCR5 binding, in addition to the V3 loop itself, indicating a two-element binding site on gp120 for CCR5. gp120 mutagenesis; CCR5 binding assay Science High 9632396
1999 The N-terminal region of CCR5 undergoes post-translational modification by O-linked glycosylation and tyrosine sulfation; sulfated N-terminal tyrosines contribute to binding of MIP-1alpha, MIP-1beta, and HIV-1 gp120/CD4 complexes and are required for efficient HIV-1 entry. Sulfation inhibition (chlorate treatment); tyrosine-to-phenylalanine mutagenesis; binding assay with soluble gp120/CD4; HIV-1 infection assay Cell High 10089882
1999 CD4 and CCR5 constitutively associate on the cell surface in the absence of gp120; this interaction involves the second extracellular loop of CCR5 and the first two domains of CD4 and can be inhibited by antibodies that also block HIV-1 infection. Co-immunoprecipitation; antibody competition assay; CD4/CCR5 truncation mutants Proceedings of the National Academy of Sciences Medium 10377443
1998 CCR5 internalisation is induced by RANTES but not by phorbol esters, distinguishing it from CXCR4; CCR5 lacks the Ser/IleLeu motif required for phorbol-ester-induced endocytosis, indicating distinct endocytic regulation for the two co-receptors. Flow cytometry-based receptor internalization assay; pharmacological inhibitors; receptor mutant analysis Journal of Cell Science High 9718374
1998 CCR5 functionally couples to inhibitory G proteins (Gi, specifically Gialpha2), stimulating [35S]GTPgammaS binding and inhibiting adenylyl cyclase in a pertussis-toxin-sensitive manner; brief RANTES pretreatment causes rapid receptor desensitization and prolonged exposure leads to agonist-dependent internalization. GTPγS binding assay; adenylyl cyclase inhibition assay; pertussis toxin treatment; flow cytometry for surface receptor; co-transfection with dominant Gialpha2 Journal of Cellular Biochemistry High 9736452
2000 CCR5 receptor dimerization blocks HIV-1 infection; an anti-CCR5 mAb that induces receptor dimerization (without competing with chemokine binding or triggering signaling) prevents HIV-1 replication in vitro and in vivo; chemokines also induce CCR5 dimerization and dimerization is required for their anti-HIV-1 activity. Anti-CCR5 mAb functional assay; HIV-1 replication in PBMCs; SCID mouse model; receptor dimerization detection Proceedings of the National Academy of Sciences Medium 10725362
2000 MIP-1beta stimulation of CCR5 induces formation of a signaling complex consisting of RAFTK/Pyk2, Syk, SHP1, SHP2, and Grb2; SHP1 and SHP2 undergo enhanced tyrosine phosphorylation upon CCR5 activation; RAFTK acts upstream of Syk activation; phosphatase inhibition abolishes MIP-1beta-induced chemotaxis. Co-immunoprecipitation; Western blot for phosphorylation; dominant-negative RAFTK mutants; orthovanadate phosphatase inhibitor; chemotaxis assay The Journal of Biological Chemistry Medium 10747947
2001 Eotaxin acts as an agonist for CCR5 (triggering CCR5 internalization at 100 nM) and a natural antagonist for CCR2; eotaxin displaces CCR5 ligands from monocytes and inhibits RANTES/MIP-1beta-induced migration and enzyme release via CCR5. Receptor internalization assay; 125I-MCP-1 binding competition; chemotaxis assay; calcium mobilization assay; transfected cell lines expressing CCR5 or CCR2 Blood High 11264152
2002 CCR5 internalisation after chemokine treatment occurs via clathrin-coated pits (inhibited by sucrose; accompanied by arrestin-2 redistribution) and also through caveolae (inhibited by nystatin/filipin); CCR5 recycling is independent of the Golgi apparatus and late endosomes, and likely proceeds through early endosomes; protein synthesis is not required for receptor recovery. Pharmacological inhibitors of clathrin (sucrose) and caveolae (nystatin, filipin); vesicle transport inhibitors; GFP-arrestin-2 translocation imaging; flow cytometry Blood High 11806977
2003 Both CD4 and CCR5 accumulate in actin- and ezrin-containing membrane protrusions in living cells; although they extensively co-localize in these structures, they do not exist in a stable constitutive complex. High-resolution deconvolution fluorescence microscopy of living cells Journal of Virology Medium 12663805
2004 CCR5 internalization and recycling require actin polymerization and activation of RhoGTPase family members in a Rho-dependent (but Rho kinase-independent) manner; cytochalasin D and Toxin B/C3 exoenzyme each block both CCR5 internalization and recycling. Actin depolymerization (cytochalasin D); RhoGTPase inhibitors (Toxin B, C3 exoenzyme); Rho kinase inhibitor (Y27632); flow cytometry for surface receptor levels European Journal of Biochemistry Medium 14717692
2004 CCR5 inhibitors (including aplaviroc) bind within a predominantly lipophilic pocket at the interface of extracellular loops and the upper transmembrane domain; mutations at key CCR5 residues decreased both gp120 binding and HIV-1 infectivity, while mutations in TM4/TM5 reduced gp120 binding with lesser effects on CC-chemokine binding, indicating the CCR5 inhibitor binding site partially overlaps with but is distinct from the CC-chemokine binding site. Saturation binding assays; site-directed mutagenesis of CCR5 residues; HIV-1 infection assay; structural modeling The Journal of Biological Chemistry High 16476734
2004 I-TAC/CXCL11 acts as a natural antagonist for CCR5: it inhibits MIP-1alpha binding to CCR5-transfected cells and monocytes, blocks RANTES/MIP-1beta-induced chemotaxis, and reduces CCR5-mediated intracellular calcium release and actin polymerization to minimal levels. Radioligand binding competition assay; chemotaxis assay; intracellular calcium measurement; actin polymerization assay; transfected cells and primary monocytes Journal of Leukocyte Biology High 15178708
2006 Microbial HSP70 binds directly to CCR5 extracellular peptides (demonstrated by surface plasmon resonance), stimulates CCR5-mediated calcium mobilization and p38 MAPK phosphorylation, and induces CCL5 production in CD40/CCR5-co-transfected cells; stimulation of IL-12 p40 by HSP70 is inhibited by the CCR5 antagonist TAK-779. Surface plasmon resonance (direct binding); calcium mobilization assay; p38 MAPK phosphorylation; transfected HEK293 cells; primary monocyte-derived DCs; CCR5 antagonist (TAK-779) competition European Journal of Immunology Medium 16909434
2008 CCR5 and CXCR4 physically associate in a signaling complex on T cells; simultaneous expression of and cooperation between CCR5 and CXCR4 is required for chemokine-induced T cell co-stimulation at the immunological synapse; the two receptors are recruited to the immunological synapse where they deliver co-stimulatory signals. Co-immunoprecipitation; energy transfer (FRET/BRET); immunological synapse imaging; T cell activation assays in CCR5/CXCR4-expressing cells Proceedings of the National Academy of Sciences Medium 18632580
2010 NMR analysis using methyl-directed transferred cross-saturation on CCR5 reconstituted in high-density lipoprotein particles revealed that valine 59 and valine 63 of MIP-1alpha are in close proximity to CCR5 in the ligand-receptor complex. NMR (methyl-directed transferred cross-saturation); CCR5 reconstituted into rHDL lipid particles for functional stability Journal of the American Chemical Society High 20423099
2012 CCR5 is a direct cellular receptor for Staphylococcus aureus leukotoxin ED (LukED); CCR5 is required for LukED-mediated cytotoxic killing of CCR5+ myeloid cells and T lymphocytes; CCR5 receptor antagonists (including maraviroc) block LukED-dependent cell killing; CCR5-deficient mice are largely resistant to lethal S. aureus infection. CCR5 receptor binding assay (surface plasmon resonance); cytotoxicity assay with CCR5-expressing vs. CCR5-deficient cells; pharmacological CCR5 antagonism; CCR5 knockout mouse infection model Nature High 23235831
2013 CCR5 adopts conformationally heterogeneous states at the cell surface; nucleotide-free G protein (NF-G protein)-coupled CCR5 binds native chemokines with sub-nanomolar affinity, whereas gp120/HIV-1 does not discriminate between NF-G protein-coupled and uncoupled CCR5; this conformational heterogeneity allows HIV-1 to exploit low-chemokine-affinity CCR5 conformations for entry, explaining the relatively poor antiviral activity of native chemokines. Radioligand binding assays with GTP analogs; HIV-1 infection assay; receptor endocytosis assay; CCR5 mutants abolishing G protein coupling Proceedings of the National Academy of Sciences High 23696662
2013 Crystal structure of CCR5 at 2.7 Å resolution bound to the HIV entry inhibitor maraviroc reveals a ligand-binding site within the transmembrane bundle that is distinct from proposed major recognition sites for chemokines and gp120, providing the structural basis for allosteric inhibition; comparison with CXCR4 structure suggests charge distributions and steric hindrance from residue substitutions as determinants of HIV-1 co-receptor selectivity. X-ray crystallography at 2.7 Å; structural comparison with CXCR4; molecular modeling of co-receptor-gp120-V3 complexes Science High 24030490
2014 The CCR5 mRNA contains a programmed -1 ribosomal frameshift (-1 PRF) signal directed by an mRNA pseudoknot; at least two microRNAs stimulate -1 PRF by forming a triplex RNA structure; the -1 PRF event directs ribosomes to a premature termination codon, destabilizing CCR5 mRNA through the nonsense-mediated decay (NMD) pathway, thereby regulating CCR5 protein levels. Reporter assay for -1 PRF; RNA pseudoknot mutagenesis; miRNA transfection; NMD pathway inhibition; mRNA stability assay Nature High 25043019
2018 CCR5 forms homodimers in three distinct conformational states involving transmembrane helix 5 residues; two dimeric states correspond to unliganded receptors and the inverse agonist maraviroc stabilizes a third distinct dimeric state; CCR5 dimerization is required for targeting the receptor to the plasma membrane. Receptor cross-linking; energy transfer (BRET/FRET); functional export assay; computational docking; X-ray crystallography of dimerization interfaces Science Signaling High 29739880
2009 CCR5 promotes hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent signaling pathway; CCR5 mediates profibrogenic effects in resident liver cells (including HSCs), distinct from CCR1 which acts in bone-marrow-derived cells, as demonstrated in CCR5/CCR1 chimeric and knockout mice. CCR5-deficient and CCR1-deficient mice; bone marrow chimera experiments; hepatic fibrosis models (CCl4, bile duct ligation); migration assay with PI3K inhibitors and antioxidants; macrophage infiltration quantification The Journal of Clinical Investigation High 19603542
2012 CCL5-CCR5 signaling in osteosarcoma cells activates MEK, ERK, and NF-κB pathways sequentially, resulting in upregulation of αvβ3 integrin expression and promotion of cell migration; CCR5 (but not CCR1 or CCR3) mediates CCL5-induced migration, as shown by mAb, inhibitor, and siRNA knockdown of CCR5. CCR5 mAb neutralization; specific kinase inhibitors (MEK, ERK, NF-κB); dominant-negative kinase mutants; CCR5 siRNA knockdown; CCL5 shRNA; migration assay; integrin expression by flow cytometry PLoS ONE Medium 22506069
2018 CCL4 enhances preosteoclast migration via CCR5; RANKL treatment rapidly reduces CCR5 expression on preosteoclasts via MEK and JNK signaling, and this CCR5 downregulation promotes osteoclastogenesis; IFN-γ recovers CCR5 expression and counteracts RANKL-induced CCR5 downregulation. Migration assay; osteoclast differentiation assay; MEK/JNK inhibitors; IFN-γ treatment; CCR5 expression analysis by flow cytometry/Western blot Cell Death & Disease Medium 29717113
2021 CCR5 activation in neurons promotes NLRP1-dependent pyroptosis after intracerebral hemorrhage via a CCR5/PKA/CREB/NLRP1 signaling axis; CCR5 activation (by rCCL5) suppresses PKA-Cα and p-CREB expression and upregulates NLRP1, ASC, caspase-1, and GSDMD; PKA activation reverses these effects; CCR5 antagonism with maraviroc reduces pyroptosis. In vivo mouse ICH model; intracerebroventricular injection of rCCL5 and 8-Bromo-cAMP; CREB inhibitor (666-15); Western blot; immunofluorescence; neurobehavioral testing; Fluoro-Jade C staining Stroke Medium 34719258
2021 Pericyte-secreted CCL5 activates CCR5 on glioblastoma cells to enable DNA-PKcs-mediated DNA damage repair (DDR), conferring resistance to temozolomide chemotherapy; disrupting CCL5-CCR5 paracrine signaling with maraviroc inhibits DDR and improves chemotherapeutic efficacy. Genetic pericyte depletion in GBM xenografts; CCR5 antagonism (maraviroc); Western blot for DNA-PKcs and DDR markers; survival analysis of tumor-bearing mice; patient-derived xenografts Cell Research Medium 34239070
2023 Activated microglia secrete CCL3, CCL4, and CCL5 which bind and activate neuronal CCR5, promoting mTORC1 activation, inhibiting autophagy, and impairing clearance of aggregate-prone proteins; CCR5 upregulation is self-sustaining because CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation itself; pharmacological or genetic CCR5 inhibition rescues mTORC1 hyperactivation and autophagy dysfunction in HD and tauopathy mouse models. Conditioned medium transfer (microglia to neurons); CCR5 genetic knockout and pharmacological inhibition (maraviroc); mTORC1 activity assay; autophagy flux assay; aggregate clearance; HD and tauopathy mouse models Neuron High 37105172
2023 Several new CCR5 C-terminal phosphorylation sites were identified as necessary for stable arrestin2 complex formation; structural studies revealed a pXpp phosphorylation motif (three phosphoresidues) essential for arrestin2 binding and activation; this motif is conserved across many other GPCRs and contributes to arrestin2 vs. arrestin3 isoform specificity. X-ray crystallography of arrestin2-CCR5 phosphopeptide complexes; NMR; biochemical binding assays; functional β-arrestin recruitment assays; phosphosite mutagenesis Molecular Cell High 37244255
2023 Computational free-energy simulations revealed that CCR5 forms symmetric and asymmetric homodimers using TM4-TM5 as the preferred binding interface, and also forms heterodimers with CXCR4 using TM6-TM7 interfaces; the dimeric states differ in accessibility of ligand- and G protein-binding sites, indicating dimerization as an allosteric mechanism regulating receptor activity. Coarse-grained metadynamics free-energy simulations; structural modeling Nature Communications Low 37833254
2020 eNAMPT (extracellular NAMPT/visfatin) binds CCR5 and acts as a natural antagonist: it prevents CCR5 internalization mediated by RANTES, inhibits CCR5-mediated PKC activation, and blocks RANTES-dependent calcium signaling and migration in melanoma cells without activating CCR5 signaling itself. Surface plasmon resonance (direct binding); calcium signaling assay; PKC activation assay; receptor internalization assay; migration assay; CCR5-overexpressing stable cell line Cells Medium 32098202
2019 The antisense lncRNA CCR5AS protects CCR5 mRNA from degradation by interfering with interactions between the RNA-binding protein Raly and the CCR5 3' UTR; CCR5AS knockdown or enhancement correspondingly decreases or increases CCR5 expression on CD4+ T cells; CCR5AS variation at rs1015164 (an ATF1 binding site) controls CCR5AS transcription and thereby modulates HIV infection susceptibility. CCR5AS knockdown/overexpression; RNA-IP for Raly-CCR5 mRNA interaction; CCR5 surface expression by flow cytometry; HIV infection assay in CD4+ T cells Nature Immunology Medium 31209403

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Identification of a major co-receptor for primary isolates of HIV-1. Nature 3123 8649511
1996 HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 2757 8649512
1996 Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 2494 8756719
1996 CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science (New York, N.Y.) 2371 8658171
1996 Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 2295 8751444
1996 The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 2053 8674119
2008 Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of America 1545 18490657
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Molecular cell 1260 16916647
1996 CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 1074 8906795
1996 CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 974 8906796
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
1998 A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science (New York, N.Y.) 726 9632396
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1999 Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 612 10089882
1996 Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 584 8639485
2013 Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science (New York, N.Y.) 574 24030490
2013 Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 552 24172905
2012 HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine 551 22474613
2002 Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet (London, England) 530 11809184
1997 In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nature medicine 530 9359702
1996 The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nature medicine 450 8898753
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2012 HIV: cell binding and entry. Cold Spring Harbor perspectives in medicine 416 22908191
1999 Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proceedings of the National Academy of Sciences of the United States of America 412 10393974
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2013 Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 395 24172896
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