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- PDB-7qy0: X-ray structure of furin in complex with the dichlorophenylpyridi... -

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Basic information

Entry
Database: PDB / ID: 7qy0
TitleX-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 1
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 / regulation of endopeptidase activity / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / signal peptide processing / regulation of cholesterol transport ...furin / nerve growth factor production / dibasic protein processing / plasma lipoprotein particle remodeling / NGF processing / regulation of endopeptidase activity / negative regulation of transforming growth factor beta1 production / Assembly of active LPL and LIPC lipase complexes / signal peptide processing / regulation of cholesterol transport / negative regulation of low-density lipoprotein particle receptor catabolic process / peptide biosynthetic process / cytokine precursor processing / secretion by cell / Pre-NOTCH Processing in Golgi / Synthesis and processing of ENV and VPU / nerve growth factor binding / Formation of the cornified envelope / symbiont-mediated induction of syncytium formation / Signaling by PDGF / trans-Golgi network transport vesicle / Signaling by NODAL / heparan sulfate binding / blastocyst formation / Elastic fibre formation / peptide hormone processing / zymogen activation / positive regulation of membrane protein ectodomain proteolysis / CD163 mediating an anti-inflammatory response / Activation of Matrix Metalloproteinases / regulation of protein catabolic process / Maturation of hRSV A proteins / TGF-beta receptor signaling activates SMADs / Uptake and function of anthrax toxins / Collagen degradation / Respiratory syncytial virus (RSV) attachment and entry / collagen catabolic process / extracellular matrix disassembly / regulation of signal transduction / Removal of aminoterminal propeptides from gamma-carboxylated proteins / viral life cycle / extracellular matrix organization / serine-type peptidase activity / transforming growth factor beta receptor signaling pathway / protein maturation / peptide binding / negative regulation of inflammatory response to antigenic stimulus / trans-Golgi network / serine-type endopeptidase inhibitor activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / 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 / viral protein processing / endosome membrane / 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: 1.54 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)53,68017
Polymers52,1121
Non-polymers1,56716
Water8,449469
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2250 Å2
ΔGint-56 kcal/mol
Surface area17680 Å2
Unit cell
Length a, b, c (Å)131.447, 131.447, 155.329
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-1103-

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, 484 molecules

#2: Chemical ChemComp-I0T / N-[[1-[[2-[3,5-bis(chloranyl)phenyl]-6-[6-[4-(2-methoxyethyl)piperazin-4-ium-1-yl]pyridin-3-yl]oxy-pyridin-4-yl]methyl]piperidin-1-ium-4-yl]methyl]ethanamide


Mass: 629.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42Cl2N6O3 / 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.: 6 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 469 / 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

CrystalDensity Matthews: 3.72 Å3/Da / Density % sol: 66.91 %
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: 1.54→47.1 Å / Num. obs: 116862 / % possible obs: 99.9 % / Redundancy: 19.5 % / Biso Wilson estimate: 21.15 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.209 / Net I/σ(I): 11.6
Reflection shellResolution: 1.54→1.63 Å / Mean I/σ(I) obs: 0.7 / Num. unique obs: 18509 / CC1/2: 0.323 / Rrim(I) all: 4.182

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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: 1.54→34.09 Å / SU ML: 0.1889 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 17.9479
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1725 5832 5 %
Rwork0.1493 110830 -
obs0.1504 116662 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.16 Å2
Refinement stepCycle: LAST / Resolution: 1.54→34.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3601 0 89 469 4159
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074004
X-RAY DIFFRACTIONf_angle_d1.01315489
X-RAY DIFFRACTIONf_chiral_restr0.0577586
X-RAY DIFFRACTIONf_plane_restr0.0063737
X-RAY DIFFRACTIONf_dihedral_angle_d16.03911471
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.54-1.560.36661960.343607X-RAY DIFFRACTION99.84
1.56-1.570.3312180.31233628X-RAY DIFFRACTION99.95
1.57-1.590.31542020.29773623X-RAY DIFFRACTION99.92
1.59-1.610.31661820.28383671X-RAY DIFFRACTION99.97
1.61-1.640.30161860.27483628X-RAY DIFFRACTION99.95
1.64-1.660.28451900.26923648X-RAY DIFFRACTION99.95
1.66-1.680.29041950.25443666X-RAY DIFFRACTION99.97
1.68-1.710.28122200.24233620X-RAY DIFFRACTION99.97
1.71-1.730.26292230.22163610X-RAY DIFFRACTION99.95
1.73-1.760.23971840.20573650X-RAY DIFFRACTION99.97
1.76-1.790.23261940.1843645X-RAY DIFFRACTION99.97
1.79-1.820.23542040.17263665X-RAY DIFFRACTION99.97
1.82-1.860.1961870.16683651X-RAY DIFFRACTION100
1.86-1.90.18291930.14893679X-RAY DIFFRACTION100
1.9-1.940.17391890.1363676X-RAY DIFFRACTION99.97
1.94-1.980.16851760.12973692X-RAY DIFFRACTION100
1.98-2.030.16081830.12783681X-RAY DIFFRACTION100
2.03-2.090.15811900.1223678X-RAY DIFFRACTION99.97
2.09-2.150.15511990.11163685X-RAY DIFFRACTION100
2.15-2.220.14321870.10353681X-RAY DIFFRACTION100
2.22-2.30.12941740.1063705X-RAY DIFFRACTION100
2.3-2.390.1421810.10643726X-RAY DIFFRACTION100
2.39-2.50.15541770.11463707X-RAY DIFFRACTION100
2.5-2.630.15231770.12353756X-RAY DIFFRACTION100
2.63-2.80.17411990.12733702X-RAY DIFFRACTION99.97
2.8-3.010.1522080.143723X-RAY DIFFRACTION100
3.01-3.310.15481920.13573779X-RAY DIFFRACTION100
3.31-3.790.13562020.13173786X-RAY DIFFRACTION100
3.79-4.780.13592040.13043826X-RAY DIFFRACTION100
4.78-34.090.19082200.19044036X-RAY DIFFRACTION99.67

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