Abstract
Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both β H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the β H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.
Highlights
Soluble guanylate cyclase is the receptor for nitric oxide (NO) in human
A recent cryo-electron microscopy (cryo-EM) map of M.sexta Soluble guanylate cyclase (sGC) at 5.8 Å resolution in the presence of YC-1 and NO revealed an extra density located between the β H-NOX and CC domains[8]
We confirmed that purified human α1β1 sGC can be activated by the stimulator YC-1 and riociguat (Fig. 1 and Supplementary Fig. 1)
Summary
Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. Cinaciguat occupies the haem pocket in the β H-NOX domain and sGC shows both inactive and active conformations These structures suggest a converged mechanism of sGC activation by pharmacological compounds. They are used to activate sGC where impaired NO signaling is caused by haem oxidization and the subsequent loss of haem in sGC16,17 Despite their functional importance, the structural mechanisms through which sGC stimulators and activators bind and activate sGC at high resolution have been unknown for decades, especially in the context of full-length human sGC. We investigated the structures of human α1β1 sGC in complex with the stimulator YC-1 and riociguat and the activator cinaciguat by cryo-electron microscopy (cryo-EM) These structures reveal the detailed interactions involved in sGC–ligand recognition and uncover the structural changes associated with drug binding and enzyme activation
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