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- PDB-7o22: X-ray structure of furin in complex with the guanylhydrazone-base... -

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Basic information

Entry
Database: PDB / ID: 7o22
TitleX-ray structure of furin in complex with the guanylhydrazone-based inhibitor 4 (mi359)
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 / Assembly of active LPL and LIPC lipase complexes / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / peptide biosynthetic process ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / Assembly of active LPL and LIPC lipase complexes / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / peptide biosynthetic process / negative regulation of low-density lipoprotein particle receptor catabolic process / cytokine precursor processing / Pre-NOTCH Processing in Golgi / secretion by cell / Synthesis and processing of ENV and VPU / Formation of the cornified envelope / nerve growth factor binding / Signaling by PDGF / trans-Golgi network transport vesicle / blastocyst formation / Elastic fibre formation / heparan sulfate binding / Signaling by NODAL / regulation of endopeptidase activity / peptide hormone processing / zymogen activation / positive regulation of membrane protein ectodomain proteolysis / CD163 mediating an anti-inflammatory response / regulation of protein catabolic process / Activation of Matrix Metalloproteinases / TGF-beta receptor signaling activates SMADs / Uptake and function of anthrax toxins / protein maturation / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / regulation of signal transduction / Removal of aminoterminal propeptides from gamma-carboxylated proteins / negative regulation of inflammatory response to antigenic stimulus / viral life cycle / serine-type peptidase activity / extracellular matrix organization / transforming growth factor beta receptor signaling pathway / peptide binding / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / serine-type endopeptidase inhibitor activity / trans-Golgi network / protein processing / Golgi lumen / heparin binding / peptidase activity / viral translation / endopeptidase activity / Induction of Cell-Cell Fusion / protease binding / Potential therapeutics for SARS / amyloid fibril formation / Attachment and Entry / positive regulation of viral entry into host cell / viral protein processing / endosome membrane / membrane raft / Amyloid fiber formation / Golgi membrane / serine-type endopeptidase activity / cell surface / endoplasmic reticulum / extracellular exosome / extracellular region / membrane / metal ion binding / 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, subtilisin, His-active site / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, aspartic acid 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, 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 / Serine proteases, subtilase domain profile. / Peptidase S8, subtilisin-related / Furin-like repeat / Furin-like repeats / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Growth factor receptor cysteine-rich domain superfamily / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDahms, S.O. / Brandstetter, H.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM 2730 Austria
CitationJournal: Acs Chem.Biol. / Year: 2021
Title: OFF-State-Specific Inhibition of the Proprotein Convertase Furin.
Authors: Dahms, S.O. / Haider, T. / Klebe, G. / Steinmetzer, T. / Brandstetter, H.
History
DepositionMar 30, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
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

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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)53,15113
Polymers52,1121
Non-polymers1,03912
Water7,638424
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1480 Å2
ΔGint-41 kcal/mol
Surface area17360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.976, 130.976, 155.485
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-1059-

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
#6: 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 / N-Acetylglucosamine


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, 435 molecules

#2: Chemical ChemComp-CA / CALCIUM ION


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


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical ChemComp-UYW / [azanyl-[(2E)-2-[[2-[(4-chlorophenyl)methoxy]phenyl]methylidene]hydrazinyl]methylidene]azanium


Mass: 303.767 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16ClN4O / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 424 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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

CrystalDensity Matthews: 3.69 Å3/Da / Density % sol: 66.7 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 5.5
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: Jul 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.8→47.141 Å / Num. obs: 72880 / % possible obs: 99.6 % / Redundancy: 20 % / Biso Wilson estimate: 28.35 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.191 / Net I/σ(I): 15.19
Reflection shellResolution: 1.8→1.91 Å / Mean I/σ(I) obs: 1.1 / Num. unique obs: 11497 / CC1/2: 0.55 / Rrim(I) all: 3.45

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Processing

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

5jxg


Resolution: 1.8→45.82 Å / SU ML: 0.1877 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.71
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1825 3578 4.91 %
Rwork0.169 69249 -
obs0.1696 72827 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.5 Å2
Refinement stepCycle: LAST / Resolution: 1.8→45.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3540 0 57 424 4021
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00633790
X-RAY DIFFRACTIONf_angle_d0.86285181
X-RAY DIFFRACTIONf_chiral_restr0.053561
X-RAY DIFFRACTIONf_plane_restr0.0055710
X-RAY DIFFRACTIONf_dihedral_angle_d28.21381363
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.820.36131700.32152545X-RAY DIFFRACTION98.58
1.82-1.850.30881210.30082624X-RAY DIFFRACTION98.92
1.85-1.870.31861360.29182600X-RAY DIFFRACTION98.99
1.87-1.90.28931420.2612606X-RAY DIFFRACTION99.28
1.9-1.930.2741370.25482598X-RAY DIFFRACTION99.24
1.93-1.960.26491320.23552627X-RAY DIFFRACTION99.21
1.96-20.24651140.22842629X-RAY DIFFRACTION99.06
2-2.030.2871320.20852641X-RAY DIFFRACTION99.46
2.03-2.070.17731370.1992617X-RAY DIFFRACTION99.24
2.07-2.120.19261460.18012636X-RAY DIFFRACTION99.57
2.12-2.160.19421350.16932630X-RAY DIFFRACTION99.28
2.16-2.210.17571350.16092626X-RAY DIFFRACTION99.6
2.21-2.270.17561280.16262642X-RAY DIFFRACTION99.43
2.27-2.330.18091190.15542663X-RAY DIFFRACTION99.61
2.33-2.40.15111330.1492647X-RAY DIFFRACTION99.64
2.4-2.470.18161260.15332685X-RAY DIFFRACTION99.79
2.47-2.560.16871320.14722658X-RAY DIFFRACTION99.79
2.56-2.660.17821310.14932673X-RAY DIFFRACTION99.79
2.66-2.790.17131390.15012678X-RAY DIFFRACTION99.82
2.79-2.930.18681450.15812676X-RAY DIFFRACTION99.93
2.93-3.120.16761300.16462711X-RAY DIFFRACTION100
3.12-3.360.1671570.14772681X-RAY DIFFRACTION99.96
3.36-3.690.16741490.15362713X-RAY DIFFRACTION99.97
3.69-4.230.14971460.13932745X-RAY DIFFRACTION99.86
4.23-5.330.14531500.14262763X-RAY DIFFRACTION99.97
5.33-45.820.20411560.20682935X-RAY DIFFRACTION99.39
Refinement TLS params.Method: refined / Origin x: 35.1839765992 Å / Origin y: -37.3496066186 Å / Origin z: 0.212042201591 Å
111213212223313233
T0.231591665851 Å20.0006149809076 Å20.00193225875426 Å2-0.2754738795 Å20.0217872364567 Å2--0.273480824906 Å2
L0.327898062047 °20.0256632783249 °2-0.118609321265 °2-0.615132145076 °20.261822470153 °2--0.736262031227 °2
S0.0156603777365 Å °0.0216131838541 Å °0.00287061757475 Å °-0.0625712472135 Å °-0.0171603033986 Å °0.0737558186373 Å °-0.017579962849 Å °-0.0944792676071 Å °-3.3509566876E-6 Å °
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Refine TLS-ID: 1 / Selection details: chain A / Auth asym-ID: A

IDLabel asym-IDAuth seq-IDLabel seq-ID
1A - L111 - 5741
2601 - 612

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