Structural Perspectives on the Mechanism of Soluble Guanylate Cyclase Activation

Int J Mol Sci. 2021 May 21;22(11):5439. doi: 10.3390/ijms22115439.


The enzyme soluble guanylate cyclase (sGC) is the prototypical nitric oxide (NO) receptor in humans and other higher eukaryotes and is responsible for transducing the initial NO signal to the secondary messenger cyclic guanosine monophosphate (cGMP). Generation of cGMP in turn leads to diverse physiological effects in the cardiopulmonary, vascular, and neurological systems. Given these important downstream effects, sGC has been biochemically characterized in great detail in the four decades since its discovery. Structures of full-length sGC, however, have proven elusive until very recently. In 2019, advances in single particle cryo-electron microscopy (cryo-EM) enabled visualization of full-length sGC for the first time. This review will summarize insights revealed by the structures of sGC in the unactivated and activated states and discuss their implications in the mechanism of sGC activation.

Keywords: cryo–electron microscopy; enzyme structure; nitric oxide; soluble guanylate cyclase.

Publication types

  • Review

MeSH terms

  • Animals
  • Cryoelectron Microscopy / methods
  • Cyclic GMP / metabolism
  • Humans
  • Nitric Oxide / metabolism
  • Signal Transduction / physiology
  • Soluble Guanylyl Cyclase / metabolism*


  • Nitric Oxide
  • Soluble Guanylyl Cyclase
  • Cyclic GMP