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- PDB-7d9r: Structure of huamn soluble guanylate cyclase in the riociguat and... -

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Basic information

Entry
Database: PDB / ID: 7d9r
TitleStructure of huamn soluble guanylate cyclase in the riociguat and NO-bound state
Components(Guanylate cyclase soluble subunit ...) x 2
KeywordsSIGNALING PROTEIN / soluble guanylate cyclase
Function / homology
Function and homology information


retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / 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 / trans-synaptic signaling by nitric oxide, modulating synaptic transmission / guanylate cyclase complex, soluble / 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 / H-NOX domain superfamily / Haem-NO-binding / 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 / H-NOX domain superfamily / Haem-NO-binding / 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 / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / Chem-GZO / PROTOPORPHYRIN IX CONTAINING FE / Guanylate cyclase soluble subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsChen, L. / Liu, R. / Kang, Y.
Funding support China, 4items
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, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

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Assembly

Deposited unit
A: Guanylate cyclase soluble subunit alpha-1
B: Guanylate cyclase soluble subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,7757
Polymers148,1662
Non-polymers1,6095
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14680 Å2
ΔGint-133 kcal/mol
Surface area45970 Å2

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Components

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Guanylate cyclase soluble subunit ... , 2 types, 2 molecules AB

#1: Protein Guanylate cyclase soluble subunit alpha-1 / GCS-alpha-1 / Guanylate cyclase soluble subunit alpha-3 / GCS-alpha-3 / Soluble guanylate cyclase ...GCS-alpha-1 / Guanylate cyclase soluble subunit alpha-3 / GCS-alpha-3 / Soluble guanylate cyclase large subunit


Mass: 77566.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: GenBank: AAH28384.1 / Source: (gene. exp.) Homo sapiens (human) / Gene: GUCY1A1, GUC1A3, GUCSA3, GUCY1A3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02108, guanylate cyclase
#2: Protein Guanylate cyclase soluble subunit beta-1 / GCS-beta-1 / Guanylate cyclase soluble subunit beta-3 / GCS-beta-3 / Soluble guanylate cyclase small subunit


Mass: 70599.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GUCY1B1, GUC1B3, GUCSB3, GUCY1B3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02153, guanylate cyclase

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Non-polymers , 4 types, 5 molecules

#3: Chemical ChemComp-G2P / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-CPP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION / Magnesium


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#6: Chemical ChemComp-GZO / methyl ~{N}-[4,6-bis(azanyl)-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-~{N}-methyl-carbamate / Riociguat


Mass: 422.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19FN8O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human soluble guanylate cyclaseSoluble guanylyl cyclase
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
EM softwareName: RELION / Version: 3 / Category: 3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 215573 / Symmetry type: POINT
RefinementResolution: 3.3→229.9 Å / SU ML: 1.09 / σ(F): 0.27 / Phase error: 47.98 / Stereochemistry target values: MLHL /
Num. reflection% reflection
obs708090 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038379
ELECTRON MICROSCOPYf_angle_d0.51211398
ELECTRON MICROSCOPYf_dihedral_angle_d6.8335962
ELECTRON MICROSCOPYf_chiral_restr0.041339
ELECTRON MICROSCOPYf_plane_restr0.0031433

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