Abstract
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.
Highlights
Soluble guanylate cyclase is a nitric oxide (NO)-responsive enzyme that serves as a source of the secondary messenger cyclic guanosine monophosphate in humans and other higher eukaryotes [1]
The structural the heme ligation state is different for isolated H-NOX domains than it is for full-length and mutagenesis data on β-Asp106 suggest that this residue plays an important role in Soluble guanylate cyclase (sGC)
The rearrangements that occur in the coiled coil (CC) domains upon activation appear to beetcritical communicating the aligation state of the
Summary
Soluble guanylate cyclase (sGC) is a nitric oxide (NO)-responsive enzyme that serves as a source of the secondary messenger cyclic guanosine monophosphate (cGMP) in humans and other higher eukaryotes [1]. Upon NO binding to sGC, the rate of cGMP formation increases by several hundred-fold, effectively amplifying the initial NO signal. Dysregulation of the NO-sGC-cGMP signaling pathway is associated with various disease pathologies, including hypertension, cardiovascular diseases, neurodegenerative diseases, and asthma [4,5,6,7,8]. The first sGC-targeted drug, Adempas® , was approved by the US Food and Drug Administration in 2013 [9]. Given this clinical relevance, sGC has received considerable attention over the years, with research efforts aimed at better understanding the complex mechanism of activity regulation. Biochemical aspects of sGC activation and deactivation have been reviewed recently [10] and this review will focus on recent and exciting advances in our knowledge of sGC from a structural perspective
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