Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama, 230-0045, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.
Nat Commun. 2023 Jul 11;14(1):4107. doi: 10.1038/s41467-023-39799-2.
Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and phagocytose bacteria. The chemokine CXCL8 (also known as interleukin-8, abbreviated IL-8) and its G-protein-coupled receptors CXCR1 and CXCR2 are crucial elements in this process, and also the development of many cancers. These GPCRs have therefore been the target of many drug development campaigns and structural studies. Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. Unlike the closely related CXCR2, CXCR1 strongly prefers to bind CXCL8 in its monomeric form. The model shows that steric clashes would form between dimeric CXCL8 and extracellular loop 2 (ECL2) of CXCR1. Consistently, transplanting ECL2 of CXCR2 onto CXCR1 abolishes the selectivity for the monomeric chemokine. Our model and functional analysis of various CXCR1 mutants will assist efforts in structure-based drug design targeting specific CXC chemokine receptor subtypes.
中性粒细胞在先天免疫和塑造适应性免疫反应中发挥着关键作用。它们被趋化因子吸引到感染和组织损伤部位，在那里杀死和吞噬细菌。趋化因子 CXCL8（也称为白细胞介素-8，简称 IL-8）及其 G 蛋白偶联受体 CXCR1 和 CXCR2 是这个过程的关键要素，也是许多癌症的发展的关键要素。因此，这些 GPCR 一直是许多药物开发活动和结构研究的目标。在这里，我们使用 cryo-EM 解决了 CXCR1 与 CXCL8 和同源 G 蛋白复合物的结构，展示了受体、趋化因子和 Gαi 蛋白之间的详细相互作用。与密切相关的 CXCR2 不同，CXCR1 强烈倾向于以单体形式结合 CXCL8。该模型表明，二聚体 CXCL8 和 CXCR1 的细胞外环 2（ECL2）之间会形成空间冲突。一致地，将 CXCR2 的 ECL2 移植到 CXCR1 上会消除对单体趋化因子的选择性。我们的模型和对各种 CXCR1 突变体的功能分析将有助于基于结构的药物设计，以针对特定的 CXC 趋化因子受体亚型。
