7D9T

Structure of human soluble guanylate cyclase in the cinciguat-bound inactive state

Summary for 7D9T

• Entry DOI: 10.2210/pdb7d9t/pdb
• EMDB information: 30620
• Descriptor: Guanylate cyclase soluble subunit alpha-1, Guanylate cyclase soluble subunit beta-1, 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid (3 entities in total)
• Functional Keywords: soluble guanylate cyclase, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 148731.50

Authors

Chen, L.,Liu, R.,Kang, Y. (deposition date: 2020-10-14, release date: 2021-08-11, Last modification date: 2024-05-29)

Primary citation

Liu, R.,Kang, Y.,Chen, L.
Activation mechanism of human soluble guanylate cyclase by stimulators and activators.
Nat Commun, 12:5492-5492, 2021

PubMed 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.

PubMed: 34535643
DOI: 10.1038/s41467-021-25617-0

Experimental method

ELECTRON MICROSCOPY (4.1 Å)