The heart, in addition to its primary role in blood circulation, functions as an endocrine organ by producing cardiac hormone natriuretic peptides. These hormones regulate blood pressure through the single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor 1. The binding of the peptide hormones to the extracellular domain of the receptor activates the intracellular guanylyl cyclase domain of the receptor to produce the second messenger cyclic guanosine monophosphate. Despite their importance, the detailed architecture and domain interactions within full-length GC-A remain elusive. Here we present cryo-electron microscopy structures, functional analyses and molecular dynamics simulations of full-length human GC-A, in both the absence and the presence of atrial natriuretic peptide. The data reveal the architecture of full-length GC-A, highlighting the spatial arrangement of its various functional domains. This insight is crucial for understanding how different parts of the receptor interact and coordinate during activation. The study elucidates the molecular basis of how extracellular signals are transduced across the membrane to activate the intracellular guanylyl cyclase domain.

心脏除了在血液循环中的主要作用外，还通过产生心脏激素利钠肽来发挥内分泌器官的作用。这些激素通过单次跨膜受体鸟苷酸环化酶 A （GC-A），也称为利钠肽受体 1 来调节血压。肽激素与受体胞外结构域的结合激活受体的细胞内鸟苷酸环化酶结构域，产生第二个信使环磷酸鸟苷。尽管它们很重要，但全长 GC-A 中的详细架构和域交互仍然难以捉摸。在这里，我们介绍了在不存在和存在心房利钠肽的情况下全长人 GC-A 的冷冻电子显微镜结构、功能分析和分子动力学模拟。数据揭示了全长 GC-A 的结构，突出了其各个功能域的空间布局。这种洞察力对于理解受体的不同部分在激活过程中如何相互作用和协调至关重要。该研究阐明了细胞外信号如何跨膜转导以激活细胞内鸟苷酸环化酶结构域的分子基础。