Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer 1 . Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition 2 – 4 , less is known about endogenous chemokine-induced receptor activation and G-protein coupling. Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with G i protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. Our results reveal a unique shallow mode of binding between CXCL8 and CXCR2, and also show the interactions between CXCR2 and G i protein. Further structural analysis of the inactive and active states of CXCR2 reveals a distinct activation process and the competitive small-molecule antagonism of chemokine receptors. In addition, our results provide insights into how a G-protein-coupled receptor is activated by an endogenous protein molecule, which will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles. Structures of the G i -coupled CXC chemokine receptor 2 (CXCR2) in complex with CXCL8 and in complex with an allosteric antagonist provide insight into the ligand binding and activation of CXCR2 and its mode of G-protein coupling.

中文翻译：

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CXC趋化因子受体2激活和信号传导的结构基础

趋化因子及其受体介导细胞迁移，从而影响多种基本生物过程和疾病状况，例如炎症和癌症 1。尽管在趋化因子受体和受体-趋化因子识别 2-4 的结构研究中投入了大量精力，但对内源性趋化因子诱导的受体激活和 G 蛋白偶联知之甚少。在这里，我们展示了与 G i 蛋白复合的白细胞介素 8（IL-8，也称为 CXCL8）激活的人 CXC 趋化因子受体 2（CXCR2）的低温电子显微镜结构，以及结合到设计的变构拮抗剂。我们的结果揭示了 CXCL8 和 CXCR2 之间独特的浅层结合模式，并且还显示了 CXCR2 和 G i 蛋白之间的相互作用。对 CXCR2 的非活性和活性状态的进一步结构分析揭示了一个独特的激活过程和趋化因子受体的竞争性小分子拮抗作用。此外，我们的研究结果提供了对 G 蛋白偶联受体如何被内源性蛋白质分子激活的见解，这将有助于合理开发靶向趋化因子系统的疗法以获得更好的药理学特征。与 CXCL8 复合和与变构拮抗剂复合的 G i 偶联 CXC 趋化因子受体 2 (CXCR2) 的结构提供了对 CXCR2 的配体结合和激活及其 G 蛋白偶联模式的深入了解。我们的研究结果提供了对 G 蛋白偶联受体如何被内源性蛋白质分子激活的见解，这将有助于合理开发靶向趋化因子系统的疗法以获得更好的药理学特征。与 CXCL8 复合和与变构拮抗剂复合的 G i 偶联 CXC 趋化因子受体 2 (CXCR2) 的结构提供了对 CXCR2 的配体结合和激活及其 G 蛋白偶联模式的深入了解。我们的研究结果提供了对 G 蛋白偶联受体如何被内源性蛋白质分子激活的见解，这将有助于合理开发靶向趋化因子系统的疗法以获得更好的药理学特征。与 CXCL8 复合和与变构拮抗剂复合的 G i 偶联 CXC 趋化因子受体 2 (CXCR2) 的结构提供了对 CXCR2 的配体结合和激活及其 G 蛋白偶联模式的深入了解。