CXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12
Zhiying Zhang1, Hongwei Zhang2, Lyuqin Zheng3
1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. zhangz7@mskcc.org.
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. 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-gp120HIV-2 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 gp120HIV-2 V3 loops, explain its inhibitory effect. Docking analyses of other HIV antagonists further clarify their mechanisms. The CXCR4-gp120HIV-1 model illustrate how V3 loop residues define co-receptor specificity, offering insights into co-receptor switching and therapeutic design.
Insights
Researchers used cryo-EM to study how HIV-2 uses the CXCR4 co-receptor, finding that CXCL12 binding inhibits entry. This reveals structural details for developing new HIV therapies targeting co-receptor interactions.
Area of Science:
- Structural Biology
- Virology
- Immunology
Background:
- CCR5 and CXCR4 are key HIV co-receptors, with CXCR4 being less understood.
- CXCR4 binds CXCL12, regulating cell functions and HIV entry, which CXCL12 itself inhibits.
Purpose of the Study:
- To investigate HIV-2 envelope (Env) spike recognition by CXCR4 using cryo-electron microscopy (cryo-EM).
- To elucidate the inhibitory mechanism of CXCL12 on HIV-2 entry mediated by CXCR4.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine structures of CXCR4 alone and in complex with CXCL12 and HIV-2 gp120.
- Molecular docking analyses to study HIV antagonist mechanisms.
Main Results:
- CXCR4 forms an unexpected tetramer in both apo and complex states.
- CXCR4 binds CXCL12 with 4:8 and 8:8 stoichiometries, with the CXCL12 N-terminus entering the CXCR4 pocket.
- HIV-2 gp120 binds to the CXCR4 tetramer, with the V3 loop interacting deeply within the receptor pocket; CXCL12 binding inhibits this interaction.
Conclusions:
- The N-terminus of CXCL12 physically clashes with the HIV-2 gp120 V3 loop, explaining its inhibitory effect.
- Structural insights into CXCR4-gp120 interactions inform understanding of co-receptor specificity and switching.
- Findings provide a basis for designing novel therapeutics targeting HIV co-receptor interactions.
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