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TitleCXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8653, Year 2025
Publish dateSep 30, 2025
AuthorsZhiying Zhang / Hongwei Zhang / Lyuqin Zheng / Shihua Chen / Shuo Du / Junyu Xiao / Dinshaw J Patel /
PubMed AbstractCCR5 and CXCR4 both act as HIV co-receptors, though CXCR4 is less explored. CXCR4 binds the chemokine CXCL12 to regulate cellular processes and mediate HIV entry, a process that CXCL12 inhibits. ...CCR5 and CXCR4 both act as HIV co-receptors, though CXCR4 is less explored. CXCR4 binds the chemokine CXCL12 to regulate cellular processes and mediate HIV entry, a process that CXCL12 inhibits. Using cryo-EM, we investigate HIV-2 envelope (Env) spike recognition by CXCR4 and how CXCL12 inhibit this interaction. We discover that CXCR4 unexpected forms a tetramer, both alone and in complex. It binds CXCL12 with 4:8 and 8:8 stoichiometries, with the CXCL12 N-terminus inserting into the CXCR4 pocket. Structures of CXCR4-gp120 complex show one or two gp120 molecules per CXCR4 tetramer, with the V3 loop occupying the major sub-pocket of CXCR4 through deep embedment of its GFKF motif. The CXCL12 N-terminus chashes with gp120 V3 loops, explain its inhibitory effect. Docking analyses of other HIV antagonists further clarify their mechanisms. The CXCR4-gp120 model illustrate how V3 loop residues define co-receptor specificity, offering insights into co-receptor switching and therapeutic design.
External linksNat Commun / PubMed:41027939 / PubMed Central
MethodsEM (single particle)
Resolution3.37 - 5.65 Å
Structure data

EMDB-48182, PDB-9me1:
hCXCR4-CXCL12 complex with 1:1 stoichiometry
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-48215, PDB-9mej:
Global structure of hCXCR4 and HIV-2 gp120
Method: EM (single particle) / Resolution: 3.99 Å

EMDB-48218: cryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop
PDB-9men: CryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-48219, PDB-9met:
CXCR4-HIV-2/gp120-CD4
Method: EM (single particle) / Resolution: 5.65 Å

EMDB-48220, PDB-9meu:
CXCR4 tetramer bound to 4 CXCL12 dimers
Method: EM (single particle) / Resolution: 3.46 Å

Source
  • homo sapiens (human)
  • human immunodeficiency virus 2
  • virus-associated rnas
  • Cronobacter phage ES2 (virus)
KeywordsSIGNALING PROTEIN / HIV block / GPCR / HIV-2 / gp120 / CXCR4 / receptor / HIV-2 gp120 / V3 loop / hCXCR4 / CD4 / D1-D2 / CXCL12

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