8K3Z

Cryo-EM structure of CXCR4 in complex with CXCL12

Summary for 8K3Z

• Entry DOI: 10.2210/pdb8k3z/pdb
• EMDB information: 36869
• Descriptor: C-X-C chemokine receptor type 4, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (6 entities in total)
• Functional Keywords: chemokine receptor, cxcr4, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 151200.79

Authors

Liu, Y.Z.,Liu, A.J.,Liao, Q.W.,Ye, R.D. (deposition date: 2023-07-17, release date: 2024-07-17, Last modification date: 2025-01-29)

Primary citation

Liu, Y.,Liu, A.,Li, X.,Liao, Q.,Zhang, W.,Zhu, L.,Ye, R.D.
Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state.
Cell Rep, 43:114578-114578, 2024

PubMed Abstract: CXCR4 binding of its endogenous agonist CXCL12 leads to diverse functions, including bone marrow retention of hematopoietic progenitors and cancer metastasis. However, the structure of the CXCL12-bound CXCR4 remains unresolved despite available structures of CXCR4 in complex with antagonists. Here, we present the cryoelectron microscopy (cryo-EM) structure of the CXCL12-CXCR4-Gi complex at an overall resolution of 2.65 Å. CXCL12 forms a 1:1 stoichiometry complex with CXCR4, following the two-site model. The first 8 amino acids of mature CXCL12 are crucial for CXCR4 activation by forming polar interactions with minor sub-pocket residues in the transmembrane binding pocket. The 3.2-Å distance between V3 of CXCL12 and the "toggle switch" W marks the deepest insertion among all chemokine-receptor pairs, leading to conformational changes of CXCR4 for G protein activation. These results, combined with functional assays and computational analysis, provide the structural basis for CXCR4 activation by CXCL12.

PubMed: 39093700
DOI: 10.1016/j.celrep.2024.114578

Experimental method

ELECTRON MICROSCOPY (2.81 Å)