Author response: Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO.

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Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy

10.1101/729418 ◽

2019 ◽

Author(s):

Benjamin G. Horst ◽

Adam L. Yokom ◽

Daniel J. Rosenberg ◽

Kyle L. Morris ◽

Michal Hammel ◽

...

Keyword(s):

Nitric Oxide ◽

Electron Microscopy ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Coiled Coil ◽

X Ray ◽

Nitric Oxide Signaling ◽

Catalytic Domains ◽

X Ray Scattering ◽

Cryo Electron Microscopy

AbstractSoluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-lengthManduca sextasGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO.

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Activation mechanism of human soluble guanylate cyclase by stimulators and activators

Nature Communications ◽

10.1038/s41467-021-25617-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Rui Liu ◽

Yunlu Kang ◽

Lei Chen

Keyword(s):

Electron Microscopy ◽

Guanylate Cyclase ◽

Drug Target ◽

Soluble Guanylate Cyclase ◽

Activation Mechanism ◽

Active Conformation ◽

Cryo Electron Microscopy ◽

Human Soluble Guanylate Cyclase ◽

Structural Mechanisms ◽

Sgc Stimulators

AbstractSoluble 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.

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