Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.

趋化因子受体 CXCR4 通过其趋化因子配体 CXCL12 激活，调节多种细胞过程。先前报道的 CXCR4 晶体结构揭示了无活性的同型二聚体受体的结构。然而，CXCR4 的许多结构方面仍然知之甚少。在这里，我们使用冷冻电子显微镜来研究人类 CXCR4 调节的各种模式。 CXCL12 通过将其 N 末端深深插入 CXCR4 正位袋来激活 CXCR4。美国食品和药物管理局批准的拮抗剂 AMD3100 的结合通过与七跨膜螺旋束中的酸性残基的静电相互作用来稳定。 REGN7663 是一种有效的抗体阻断剂，可与 CXCR4 的胞外面结合，并将其互补决定区 H3 环插入正构口袋中。 CXCR4 的三聚体和四聚体结构揭示了 G 蛋白偶联受体寡聚化的模式。我们证明 CXCR4 在三聚体和四聚体组装中采用不同的亚基构象，强调寡聚化如何变构调节趋化因子受体功能。