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| Title | Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state. |
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| Journal, issue, pages | Cell Rep, Vol. 43, Issue 8, Page 114578, Year 2024 |
| Publish date | Aug 27, 2024 |
 Authors | Yezhou Liu / Aijun Liu / Xinyu Li / Qiwen Liao / Weijia Zhang / Lizhe Zhu / Richard D Ye /  |
| 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- ...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. |
 External links | Cell Rep / PubMed:39093700 |
| Methods | EM (single particle) |
| Resolution | 2.81 Å |
| Structure data | EMDB-36869, PDB-8k3z: |
| Source |
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 Keywords | IMMUNE SYSTEM / Chemokine receptor / CXCR4 |
homo sapiens (human)
vicugna pacos (alpaca)