Unveiling the Structure and Activation Mechanisms of Full-length ANPR

The heart extends beyond its fundamental role in circulating blood, doubling as an endocrine organ through the secretion of cardiac natriuretic peptides. These peptides orchestrate blood pressure regulation via the natriuretic peptide receptor-1 (NPR1), known alternatively as NPR-A, ANPR, or GC-A. They achieve this by binding to the receptor's extracellular domain, subsequently activating its intracellular guanylyl cyclase domain to generate the second messenger, cyclic guanosine monophosphate (cGMP). However, the intricate architecture and the domain interactions of full-length GC-A have remained obscure. This investigation employs cryo-electron microscopy, functional analyses, and molecular dynamics simulations to explore the structure of full-length human GC-A in both the absence and presence of atrial natriuretic peptide (ANP). Our results reveal the sophisticated architecture and regulatory mechanisms of this single-pass transmembrane receptor guanylyl cyclase, shedding light on its functional dynamics and unveiling potential therapeutic avenues.