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- EMDB-30620: Structure of human soluble guanylate cyclase in the cinciguat-bou... -

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Basic information

Entry
Database: EMDB / ID: EMD-30620
TitleStructure of human soluble guanylate cyclase in the cinciguat-bound inactive state
Map data
Samplehuman soluble guanylate cyclaseSoluble guanylyl cyclase
  • (Guanylate cyclase soluble subunit ...) x 2
  • ligand
Function / homology
Function and homology information


retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cGMP biosynthetic process / guanylate cyclase / guanylate cyclase activity / Nitric oxide stimulates guanylate cyclase / blood circulation / relaxation of vascular associated smooth muscle / cGMP-mediated signaling ...retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cGMP biosynthetic process / guanylate cyclase / guanylate cyclase activity / Nitric oxide stimulates guanylate cyclase / blood circulation / relaxation of vascular associated smooth muscle / cGMP-mediated signaling / presynaptic active zone / nitric oxide-cGMP-mediated signaling pathway / Smooth Muscle Contraction / GABA-ergic synapse / cellular response to nitric oxide / positive regulation of nitric oxide mediated signal transduction / nitric oxide mediated signal transduction / regulation of blood pressure / signaling receptor activity / glutamatergic synapse / GTP binding / heme binding / metal ion binding
Similarity search - Function
Haem NO binding associated domain superfamily / Haem NO binding associated / Heme NO binding associated / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Heme NO-binding / Haem-NO-binding / H-NOX domain superfamily / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain ...Haem NO binding associated domain superfamily / Haem NO binding associated / Heme NO binding associated / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Heme NO-binding / Haem-NO-binding / H-NOX domain superfamily / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Guanylate cyclase domain profile. / Adenylyl cyclase class-3/4/guanylyl cyclase / Nucleotide cyclase
Similarity search - Domain/homology
Guanylate cyclase soluble subunit alpha-1 / Guanylate cyclase soluble subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsChen L / Liu R / Kang Y
Funding support China, 4 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2016YFA0502004 China
National Natural Science Foundation of China (NSFC)31622021 China
National Natural Science Foundation of China (NSFC)31821091 China
National Natural Science Foundation of China (NSFC)31870833 China
CitationJournal: Nat Commun / Year: 2021
Title: Activation mechanism of human soluble guanylate cyclase by stimulators and activators.
Authors: Rui Liu / Yunlu Kang / Lei Chen /
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 ...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.
History
DepositionOct 14, 2020-
Header (metadata) releaseAug 11, 2021-
Map releaseAug 11, 2021-
UpdateOct 13, 2021-
Current statusOct 13, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0296
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0296
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7d9t
  • Surface level: 0.0296
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30620.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 240 pix.
= 250.8 Å
1.05 Å/pix.
x 240 pix.
= 250.8 Å
1.05 Å/pix.
x 240 pix.
= 250.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.0296 / Movie #1: 0.0296
Minimum - Maximum-0.04514336 - 0.12823412
Average (Standard dev.)0.00030232663 (±0.0030099202)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 250.79999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z250.800250.800250.800
α/β/γ90.00090.00090.000
start NX/NY/NZ594743
NX/NY/NZ375263
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0450.1280.000

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Supplemental data

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Sample components

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Entire human soluble guanylate cyclase

EntireName: human soluble guanylate cyclaseSoluble guanylyl cyclase
Number of Components: 4

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Component #1: protein, human soluble guanylate cyclase

ProteinName: human soluble guanylate cyclaseSoluble guanylyl cyclase
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #2: protein, Guanylate cyclase soluble subunit alpha-1

ProteinName: Guanylate cyclase soluble subunit alpha-1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 77.566484 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, Guanylate cyclase soluble subunit beta-1

ProteinName: Guanylate cyclase soluble subunit beta-1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 70.59932 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: ligand, 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}p...

LigandName: 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.565699 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationCryogen Name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 50 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 QUANTUM (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of Projections: 244400
3D reconstructionSoftware: RELION / Resolution: 4.1 Å / Resolution Method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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