9MEN

CryoEM structure of hCXCR4 tetramer bound to HIV-2/gp120/V3 loop

Summary for 9MEN

• Entry DOI: 10.2210/pdb9men/pdb
• EMDB information: 48218
• Descriptor: C-X-C chemokine receptor type 4, Surface protein gp120 (2 entities in total)
• Functional Keywords: hiv-2 gp120, v3 loop, hcxcr4, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 165399.16

Authors

Zhang, Z.,Patel, D.J. (deposition date: 2024-12-07, release date: 2025-09-10, Last modification date: 2026-03-25)

Primary citation

Zhang, Z.,Zhang, H.,Zheng, L.,Chen, S.,Du, S.,Xiao, J.,Patel, D.J.
CXCR4 mediated recognition of HIV envelope spike and inhibition by CXCL12.
Nat Commun, 16:8653-8653, 2025

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. 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.

PubMed: 41027939
DOI: 10.1038/s41467-025-63815-2

Experimental method

ELECTRON MICROSCOPY (3.57 Å)