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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
Sample
  • Complex: human soluble guanylate cyclase
    • Protein or peptide: Guanylate cyclase soluble subunit alpha-1
    • Protein or peptide: Guanylate cyclase soluble subunit beta-1
  • Ligand: 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid
Keywordssoluble guanylate cyclase / SIGNALING PROTEIN
Function / homology
Function and homology information


retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cytidylate cyclase activity / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / guanylate cyclase / cGMP biosynthetic process / guanylate cyclase activity / presynaptic active zone cytoplasmic component / response to oxygen levels / Nitric oxide stimulates guanylate cyclase ...retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cytidylate cyclase activity / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / guanylate cyclase / cGMP biosynthetic process / guanylate cyclase activity / presynaptic active zone cytoplasmic component / response to oxygen levels / Nitric oxide stimulates guanylate cyclase / relaxation of vascular associated smooth muscle / adenylate cyclase activity / blood circulation / cGMP-mediated signaling / positive regulation of nitric oxide mediated signal transduction / Smooth Muscle Contraction / cellular response to nitric oxide / nitric oxide mediated signal transduction / GABA-ergic synapse / nitric oxide-cGMP-mediated signaling / Hsp90 protein binding / regulation of blood pressure / signaling receptor activity / glutamatergic synapse / heme binding / protein-containing complex binding / GTP binding / metal ion binding / cytosol
Similarity search - Function
Haem NO binding associated / Haem NO binding associated domain superfamily / Heme NO binding associated / Heme NO-binding / H-NOX domain superfamily / Haem-NO-binding / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain ...Haem NO binding associated / Haem NO binding associated domain superfamily / Heme NO binding associated / Heme NO-binding / H-NOX domain superfamily / Haem-NO-binding / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / NO signalling/Golgi transport ligand-binding domain superfamily / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / 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
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-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing 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
  • Download
  • 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

emd_30620.png

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

Histogram

Histogram (log scale)
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 cyclase
Components
  • Complex: human soluble guanylate cyclase
    • Protein or peptide: Guanylate cyclase soluble subunit alpha-1
    • Protein or peptide: Guanylate cyclase soluble subunit beta-1
  • Ligand: 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid

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Supramolecule #1: human soluble guanylate cyclase

SupramoleculeName: human soluble guanylate cyclase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanylate cyclase soluble subunit alpha-1

MacromoleculeName: Guanylate cyclase soluble subunit alpha-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: guanylate cyclase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.566484 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MFCTKLKDLK ITGECPFSLL APGQVPNESS EEAAGSSESC KATMPICQDI PEKNIQESLP QRKTSRSRVY LHTLAESICK LIFPEFERL NVALQRTLAK HKIKESRKSL EREDFEKTIA EQAVAAGVPV EVIKESLGEE VFKICYEEDE NILGVVGGTL K DFLNSFST ...String:
MFCTKLKDLK ITGECPFSLL APGQVPNESS EEAAGSSESC KATMPICQDI PEKNIQESLP QRKTSRSRVY LHTLAESICK LIFPEFERL NVALQRTLAK HKIKESRKSL EREDFEKTIA EQAVAAGVPV EVIKESLGEE VFKICYEEDE NILGVVGGTL K DFLNSFST LLKQSSHCQE AGKRGRLEDA SILCLDKEDD FLHVYYFFPK RTTSLILPGI IKAAAHVLYE TEVEVSLMPP CF HNDCSEF VNQPYLLYSV HMKSTKPSLS PSKPQSSLVI PTSLFCKTFP FHFMFDKDMT ILQFGNGIRR LMNRRDFQGK PNF EEYFEI LTPKINQTFS GIMTMLNMQF VVRVRRWDNS VKKSSRVMDL KGQMIYIVES SAILFLGSPC VDRLEDFTGR GLYL SDIPI HNALRDVVLI GEQARAQDGL KKRLGKLKAT LEQAHQALEE EKKKTVDLLC SIFPCEVAQQ LWQGQVVQAK KFSNV TMLF SDIVGFTAIC SQCSPLQVIT MLNALYTRFD QQCGELDVYK VETIGDAYCV AGGLHKESDT HAVQIALMAV KMMELS DEV MSPHGEPIKM RIGLHSGSVF AGVVGVKMPR YCLFGNNVTL ANKFESCSVP RKINVSPTTY RLLKDCPGFV FTPRSRE EL PPNFPSEIPG ICHFLDAYQQ GTNSKPCFQK KDVEDGNANF LGKASGID

UniProtKB: Guanylate cyclase soluble subunit alpha-1

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Macromolecule #2: Guanylate cyclase soluble subunit beta-1

MacromoleculeName: Guanylate cyclase soluble subunit beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: guanylate cyclase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.59932 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MYGFVNHALE LLVIRNYGPE VWEDIKKEAQ LDEEGQFLVR IIYDDSKTYD LVAAASKVLN LNAGEILQMF GKMFFVFCQE SGYDTILRV LGSNVREFLQ NLDALHDHLA TIYPGMRAPS FRCTDAEKGK GLILHYYSER EGLQDIVIGI IKTVAQQIHG T EIDMKVIQ ...String:
MYGFVNHALE LLVIRNYGPE VWEDIKKEAQ LDEEGQFLVR IIYDDSKTYD LVAAASKVLN LNAGEILQMF GKMFFVFCQE SGYDTILRV LGSNVREFLQ NLDALHDHLA TIYPGMRAPS FRCTDAEKGK GLILHYYSER EGLQDIVIGI IKTVAQQIHG T EIDMKVIQ QRNEECDHTQ FLIEEKESKE EDFYEDLDRF EENGTQESRI SPYTFCKAFP FHIIFDRDLV VTQCGNAIYR VL PQLQPGN CSLLSVFSLV RPHIDISFHG ILSHINTVFV LRSKEGLLDV EKLECEDELT GTEISCLRLK GQMIYLPEAD SIL FLCSPS VMNLDDLTRR GLYLSDIPLH DATRDLVLLG EQFREEYKLT QELEILTDRL QLTLRALEDE KKKTDTLLYS VLPP SVANE LRHKRPVPAK RYDNVTILFS GIVGFNAFCS KHASGEGAMK IVNLLNDLYT RFDTLTDSRK NPFVYKVETV GDKYM TVSG LPEPCIHHAR SICHLALDMM EIAGQVQVDG ESVQITIGIH TGEVVTGVIG QRMPRYCLFG NTVNLTSRTE TTGEKG KIN VSEYTYRCLM SPENSDPQFH LEHRGPVSMK GKKEPMQVWF LSRKNTGTEE TKQDDD

UniProtKB: Guanylate cyclase soluble subunit beta-1

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Macromolecule #3: 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)et...

MacromoleculeName: 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid
type: ligand / ID: 3 / Number of copies: 1 / Formula: Z90
Molecular weightTheoretical: 565.699 Da
Chemical component information

ChemComp-Z90:
4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 244400
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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