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- PDB-7qy1: X-ray structure of furin in complex with the dichlorophenylpyridi... -

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Basic information

Entry
Database: PDB / ID: 7qy1
TitleX-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 4
ComponentsFurin
KeywordsHYDROLASE / proprotein convertase / inhibitor / SARS-CoV-2 / protease / complex / furin
Function / homology
Function and homology information


furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / regulation of cholesterol transport / signal peptide processing / negative regulation of low-density lipoprotein particle receptor catabolic process ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / regulation of cholesterol transport / signal peptide processing / negative regulation of low-density lipoprotein particle receptor catabolic process / peptide biosynthetic process / Pre-NOTCH Processing in Golgi / nerve growth factor binding / Synthesis and processing of ENV and VPU / cytokine precursor processing / Formation of the cornified envelope / secretion by cell / Signaling by PDGF / trans-Golgi network transport vesicle / Signaling by NODAL / heparan sulfate binding / blastocyst formation / Elastic fibre formation / peptide hormone processing / positive regulation of membrane protein ectodomain proteolysis / zymogen activation / CD163 mediating an anti-inflammatory response / Activation of Matrix Metalloproteinases / Maturation of hRSV A proteins / regulation of protein catabolic process / TGF-beta receptor signaling activates SMADs / Collagen degradation / collagen catabolic process / Uptake and function of anthrax toxins / Respiratory syncytial virus (RSV) attachment and entry / extracellular matrix disassembly / regulation of signal transduction / endopeptidase activator activity / Removal of aminoterminal propeptides from gamma-carboxylated proteins / viral life cycle / extracellular matrix organization / serine-type peptidase activity / peptide binding / transforming growth factor beta receptor signaling pathway / protein maturation / negative regulation of inflammatory response to antigenic stimulus / serine-type endopeptidase inhibitor activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / trans-Golgi network / protein processing / Golgi lumen / peptidase activity / heparin binding / protease binding / endopeptidase activity / viral translation / amyloid fibril formation / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / Attachment and Entry / positive regulation of viral entry into host cell / endosome membrane / viral protein processing / membrane raft / Amyloid fiber formation / Golgi membrane / serine-type endopeptidase activity / cell surface / endoplasmic reticulum / extracellular exosome / extracellular region / metal ion binding / membrane / plasma membrane
Similarity search - Function
Peptidase S8, pro-domain / Peptidase S8, pro-domain superfamily / Peptidase S8 pro-domain / Kexin/furin catalytic domain / P domain / Proprotein convertase P-domain / P/Homo B domain profile. / Peptidase S8/S53 domain / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. ...Peptidase S8, pro-domain / Peptidase S8, pro-domain superfamily / Peptidase S8 pro-domain / Kexin/furin catalytic domain / P domain / Proprotein convertase P-domain / P/Homo B domain profile. / Peptidase S8/S53 domain / Peptidase S8, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, aspartic acid active site. / Peptidase S8, subtilisin, Asp-active site / Serine proteases, subtilase family, serine active site. / Peptidase S8, subtilisin, Ser-active site / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Galactose-binding domain-like / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Galactose-binding-like domain superfamily / Jelly Rolls / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsDahms, S.O. / Brandstetter, H. / Pautsch, A.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM 2730 Austria
CitationJournal: Acs Chem.Biol. / Year: 2022
Title: Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.
Authors: Dahms, S.O. / Schnapp, G. / Winter, M. / Buttner, F.H. / Schleputz, M. / Gnamm, C. / Pautsch, A. / Brandstetter, H.
History
DepositionJan 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Furin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,77118
Polymers52,1121
Non-polymers1,65817
Water8,521473
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2370 Å2
ΔGint-56 kcal/mol
Surface area17710 Å2
Unit cell
Length a, b, c (Å)131.191, 131.191, 155.280
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6
Components on special symmetry positions
IDModelComponents
11A-606-

NA

21A-1105-

HOH

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Furin / Dibasic-processing enzyme / Paired basic amino acid residue-cleaving enzyme / PACE


Mass: 52112.312 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FURIN, FUR, PACE, PCSK3 / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P09958, furin
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 489 molecules

#2: Chemical ChemComp-I0W / 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-ium-1-yl]propanoate


Mass: 642.596 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H39Cl2N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 473 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: CRYSTALLIZATION SOLUTION: 100mM MES, 200mM K/NAH2PO4, PH 5.5, 2 M NACL; RESERVOIR SOLUTION: 3.0-3.2M NACL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Dec 2, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.45→47.1 Å / Num. obs: 136831 / % possible obs: 98.6 % / Redundancy: 20 % / Biso Wilson estimate: 19.24 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.204 / Net I/σ(I): 13.4
Reflection shellResolution: 1.45→1.54 Å / Mean I/σ(I) obs: 0.6 / Num. unique obs: 21547 / CC1/2: 0.298 / Rrim(I) all: 5.483

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PHENIX1.18.2_3874phasing
XDSVERSION Jan 31, 2020data reduction
XDSVERSION Jan 31, 2020data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jxg

5jxg


Resolution: 1.45→36.73 Å / SU ML: 0.2033 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.8917
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1754 6802 4.98 %
Rwork0.1502 129850 -
obs0.1515 136652 98.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.78 Å2
Refinement stepCycle: LAST / Resolution: 1.45→36.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3590 0 94 473 4157
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00844003
X-RAY DIFFRACTIONf_angle_d1.0525483
X-RAY DIFFRACTIONf_chiral_restr0.0815586
X-RAY DIFFRACTIONf_plane_restr0.0065734
X-RAY DIFFRACTIONf_dihedral_angle_d14.70841469
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.470.41892200.39944189X-RAY DIFFRACTION96.82
1.47-1.480.4292180.36124234X-RAY DIFFRACTION97.48
1.48-1.50.34082110.34534218X-RAY DIFFRACTION97.49
1.5-1.520.3492210.31824248X-RAY DIFFRACTION97.45
1.52-1.540.31772150.29894228X-RAY DIFFRACTION97.5
1.54-1.560.34652230.29534234X-RAY DIFFRACTION97.78
1.56-1.580.31492600.28014220X-RAY DIFFRACTION97.8
1.58-1.610.30252110.25814223X-RAY DIFFRACTION98.05
1.61-1.630.28932180.24844254X-RAY DIFFRACTION97.81
1.63-1.660.27892240.24824291X-RAY DIFFRACTION98.19
1.66-1.690.27892450.22684234X-RAY DIFFRACTION98.03
1.69-1.720.25582430.20294252X-RAY DIFFRACTION98.42
1.72-1.750.22072490.17964292X-RAY DIFFRACTION98.25
1.75-1.790.20662190.16624243X-RAY DIFFRACTION98.35
1.79-1.830.20542420.15794289X-RAY DIFFRACTION98.59
1.83-1.870.18232100.14574311X-RAY DIFFRACTION98.63
1.87-1.920.16822340.13494305X-RAY DIFFRACTION98.74
1.92-1.970.17812070.12854330X-RAY DIFFRACTION98.78
1.97-2.030.15392090.11664341X-RAY DIFFRACTION98.96
2.03-2.090.14562250.10734341X-RAY DIFFRACTION98.96
2.09-2.170.13112330.10184337X-RAY DIFFRACTION99.07
2.17-2.250.13332240.09724362X-RAY DIFFRACTION99.07
2.25-2.360.13362080.10454389X-RAY DIFFRACTION99.27
2.36-2.480.14932060.11144440X-RAY DIFFRACTION99.51
2.48-2.630.15062080.11584412X-RAY DIFFRACTION99.48
2.63-2.840.16012450.12234402X-RAY DIFFRACTION99.66
2.84-3.120.15012210.13174464X-RAY DIFFRACTION99.7
3.12-3.570.14922570.13064461X-RAY DIFFRACTION99.87
3.58-4.50.13192380.12464544X-RAY DIFFRACTION99.92
4.5-36.730.17742580.18134762X-RAY DIFFRACTION99.66

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