Activation mechanism of human soluble guanylate cyclase by stimulators and activators.
Animals
Benzoates
/ chemistry
Binding Sites
Cell Line
Cryoelectron Microscopy
Enzyme Activation
/ drug effects
Enzyme Activators
/ chemistry
Humans
Indazoles
/ chemistry
Models, Molecular
Nitric Oxide
/ pharmacology
Protein Multimerization
Pyrazoles
/ chemistry
Pyrimidines
/ chemistry
Soluble Guanylyl Cyclase
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2021
17 09 2021
Historique:
received:
29
01
2021
accepted:
18
08
2021
entrez:
18
9
2021
pubmed:
19
9
2021
medline:
13
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34535643
doi: 10.1038/s41467-021-25617-0
pii: 10.1038/s41467-021-25617-0
pmc: PMC8448884
doi:
Substances chimiques
Benzoates
0
Enzyme Activators
0
Indazoles
0
Pyrazoles
0
Pyrimidines
0
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
154453-18-6
Nitric Oxide
31C4KY9ESH
BAY 58-2667
329773-35-5
Soluble Guanylyl Cyclase
EC 4.6.1.2
riociguat
RU3FE2Y4XI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5492Informations de copyright
© 2021. The Author(s).
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