Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β₁-adrenergic receptor (β₁-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by β₁-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which β₁-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gα_s. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the β6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.

心脏病仍然是全世界发病率和死亡率的主要原因。β ₁ -肾上腺素能受体 (β ₁ -AR) 是心脏功能的主要调节剂，在大多数心力衰竭病例中被下调。一个关键的生理过程是 β ₁ -ARs 激活异源三聚体 G 蛋白 Gs，导致心率和收缩力增加。在这里，我们使用冷冻电子显微镜和功能研究来研究 β ₁ -AR 激活 Gs 的分子机制。_{我们发现 α5-螺旋的倾斜破坏了 C-末端 α5-螺旋中 His373 侧链与 Gα s} N-末端 αN-螺旋中 Arg38 主链羰基之间的氢键. 连同涉及 α1-螺旋中的 Gln59、β6-α5 环中的 Ala352 和 α5-螺旋中的 Thr355 的另一个相互作用网络的破坏，这些构象变化可能导致 GDP 结合袋的变形。我们的数据提供了对 G 蛋白偶联受体激活 G 蛋白的分子见解。