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- EMDB-30619: Structure of huamn soluble guanylate cyclase in the YC1 and NO-bo... -

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Basic information

Entry
Database: EMDB / ID: EMD-30619
TitleStructure of huamn soluble guanylate cyclase in the YC1 and NO-bound state
Map data
Sample
  • Complex: human soluble guanylate cyclaseSoluble guanylyl cyclase
    • Protein or peptide: Guanylate cyclase soluble subunit alpha-1
    • Protein or peptide: Guanylate cyclase soluble subunit beta-1
  • Ligand: MAGNESIUM ION
  • Ligand: [5-[1-(phenylmethyl)indazol-3-yl]furan-2-yl]methanol
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER
Function / homology
Function and homology information


retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cytidylate cyclase activity / guanylate cyclase complex, soluble / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase / guanylate cyclase activity / cGMP biosynthetic process / response to oxygen levels / presynaptic active zone cytoplasmic component / Nitric oxide stimulates guanylate cyclase ...retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / cytidylate cyclase activity / guanylate cyclase complex, soluble / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase / guanylate cyclase activity / cGMP biosynthetic process / response to oxygen levels / presynaptic active zone cytoplasmic component / Nitric oxide stimulates guanylate cyclase / relaxation of vascular associated smooth muscle / adenylate cyclase activity / blood circulation / cGMP-mediated signaling / nitric oxide-cGMP-mediated signaling / GABA-ergic synapse / Smooth Muscle Contraction / cellular response to nitric oxide / positive regulation of nitric oxide mediated signal transduction / nitric oxide mediated signal transduction / 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 domain superfamily / Haem NO binding associated / 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 domain superfamily / Haem NO binding associated / 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 / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain / 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: 3.9 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: 0.0397
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0397
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7d9s
  • Surface level: 0.0397
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30619.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.0397 / Movie #1: 0.0397
Minimum - Maximum-0.09824415 - 0.21025348
Average (Standard dev.)0.00032392028 (±0.004223366)
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-0.0980.2100.000

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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
Components
  • Complex: human soluble guanylate cyclaseSoluble guanylyl cyclase
    • Protein or peptide: Guanylate cyclase soluble subunit alpha-1
    • Protein or peptide: Guanylate cyclase soluble subunit beta-1
  • Ligand: MAGNESIUM ION
  • Ligand: [5-[1-(phenylmethyl)indazol-3-yl]furan-2-yl]methanol
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER

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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)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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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 / Details: GenBank: AAH28384.1 / 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

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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

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: [5-[1-(phenylmethyl)indazol-3-yl]furan-2-yl]methanol

MacromoleculeName: [5-[1-(phenylmethyl)indazol-3-yl]furan-2-yl]methanol / type: ligand / ID: 4 / Number of copies: 1 / Formula: YC1
Molecular weightTheoretical: 304.343 Da
Chemical component information

ChemComp-YC1:
[5-[1-(phenylmethyl)indazol-3-yl]furan-2-yl]methanol

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Macromolecule #5: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 5 / Number of copies: 1 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

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Macromolecule #6: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER

MacromoleculeName: PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / type: ligand / ID: 6 / Number of copies: 1 / Formula: G2P
Molecular weightTheoretical: 521.208 Da
Chemical component information

ChemComp-G2P:
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GMP-CPP, energy-carrying molecule analogue*YM

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

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 321343

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