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| Title | CXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 8653, Year 2025 |
| Publish date | Sep 30, 2025 |
Authors | Zhiying Zhang / Hongwei Zhang / Lyuqin Zheng / Shihua Chen / Shuo Du / Junyu Xiao / Dinshaw J Patel / ![]() |
| PubMed Abstract | 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. ...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 links | Nat Commun / PubMed:41027939 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.37 - 5.65 Å |
| Structure data | EMDB-48182, PDB-9me1: EMDB-48215, PDB-9mej: EMDB-48218: cryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop EMDB-48219, PDB-9met: EMDB-48220, PDB-9meu: |
| Source |
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Keywords | SIGNALING PROTEIN / HIV block / GPCR / HIV-2 / gp120 / CXCR4 / receptor / HIV-2 gp120 / V3 loop / hCXCR4 / CD4 / D1-D2 / CXCL12 |
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homo sapiens (human)
human immunodeficiency virus 2
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