Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein–kinin system and are essential to the regulation of blood pressure, inflammation, coagulation and pain control. Des-Arg¹⁰-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed ‘bradykinin storm’, is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein-coupled complex structures of human B1R and B2R bound to des-Arg¹⁰-kallidin and bradykinin, respectively. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders and COVID-19.

缓激肽和激肽是内源性激肽激素，属于激肽释放酶-激肽系统，对调节血压、炎症、凝血和疼痛控制至关重要。Des-Arg ¹⁰ -kallidin、kallidin 的羧基末端 des-Arg 代谢物和缓激肽分别选择性地激活两种 G 蛋白偶联受体，即 1 型和 2 型缓激肽受体（B1R 和 B2R）。缓激肽受体的过度激活，称为“缓激肽风暴”，与 COVID-19 患者的肺水肿有关，表明缓激肽受体是 COVID-19 干预的重要目标。在这里，我们报告了人类 B1R 和 B2R 与 des-Arg ¹⁰结合的两种 G 蛋白偶联复杂结构-kallidin 和缓激肽，分别。结合功能分析，我们的结构揭示了配体选择性和缓激肽受体特异性激活的机制。这些发现还为指导靶向缓激肽受体的药物设计提供了框架，用于治疗炎症、心血管疾病和 COVID-19。