Structural insights into the mechanism of the human soluble guanylate cyclase

Abstract

SummarySoluble guanylate cyclase (sGC) is the primary nitric oxide (NO) sensor. It plays a central role in NO signaling and is implicated in many essential physiological processes and disease conditions. The binding of NO leads to a significant boost in sGC enzymatic activity. However, the mechanism of NO activation remains incompletely understood. Here, we report the cryo-electron microscopy structures of the human sGC α1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the NO sensor module and the catalytic module. NO binding to the β1 H-NOX domain triggers the structural rearrangement of the sensor module and the bending-straightening conformational switch of the transducer module. The resulting movement of the N-termini of the catalytic domains drives the structural changes within the catalytic module, which in turn boost sGC enzymatic activity. These observations indicate the structural framework for the mechanism of sGC activation induced by NO binding.