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- PDB-8b4w: X-ray structure of furin (PCSK3) in complex with 1H-isoindol-3-amine -

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Basic information

Entry
Database: PDB / ID: 8b4w
TitleX-ray structure of furin (PCSK3) in complex with 1H-isoindol-3-amine
ComponentsFurin
KeywordsHYDROLASE / furin / proprotein convertase subtilisin/kexin type 3 / PCSK3 / SARS-CoV-2 / inhibitor / protease / complex
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 / biological process involved in symbiotic interaction / Assembly of active LPL and LIPC lipase complexes / blastocyst formation / 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 / biological process involved in symbiotic interaction / Assembly of active LPL and LIPC lipase complexes / blastocyst formation / negative regulation of low-density lipoprotein particle receptor catabolic process / Assembly and Release of Dengue Virus Virions / peptide biosynthetic process / signal peptidase activity / secretion by cell / Pre-NOTCH Processing in Golgi / nerve growth factor binding / Synthesis and processing of ENV and VPU / cytokine precursor processing / Formation of the cornified envelope / exocytic vesicle / Signaling by PDGF / trans-Golgi network transport vesicle / GBP-mediated host defense / heparan sulfate binding / Signaling by NODAL / Elastic fibre formation / peptide hormone processing / positive regulation of membrane protein ectodomain proteolysis / CD163 mediating an anti-inflammatory response / zymogen activation / regulation of protein catabolic process / Regulation of CDH1 posttranslational processing and trafficking to plasma membrane / Activation of Matrix Metalloproteinases / endopeptidase inhibitor activity / Collagen degradation / collagen catabolic process / TGF-beta receptor signaling activates SMADs / Maturation of hRSV A proteins / extracellular matrix disassembly / Respiratory syncytial virus (RSV) attachment and entry / Uptake and function of anthrax toxins / transforming growth factor beta receptor signaling pathway / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Dengue Virus Attachment and Entry / endopeptidase activator activity / extracellular matrix organization / viral life cycle / cholesterol homeostasis / peptide binding / serine-type peptidase activity / protein processing / serine-type endopeptidase inhibitor activity / negative regulation of inflammatory response to antigenic stimulus / trans-Golgi network / protein maturation / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Golgi lumen / peptidase activity / heparin binding / protease binding / endopeptidase activity / Induction of Cell-Cell Fusion / amyloid fibril formation / Potential therapeutics for SARS / positive regulation of viral entry into host cell / Attachment and Entry / endosome membrane / viral protein processing / membrane raft / Amyloid fiber formation / serine-type endopeptidase activity / Golgi membrane / Golgi apparatus / cell surface / endoplasmic reticulum / extracellular exosome / extracellular region / 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, 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 / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
1H-isoindol-3-amine / Furin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsDahms, S.O. / Brandstetter, H.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM 2730 Austria
CitationJournal: Chemmedchem / Year: 2024
Title: Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors.
Authors: Lange, R.W. / Bloch, K. / Heindl, M.R. / Wollenhaupt, J. / Weiss, M.S. / Brandstetter, H. / Klebe, G. / Falcone, F.H. / Bottcher-Friebertshauser, E. / Dahms, S.O. / Steinmetzer, T.
History
DepositionSep 21, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 4, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID
Revision 1.3Nov 13, 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)53,21216
Polymers52,1121
Non-polymers1,10015
Water8,881493
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1640 Å2
ΔGint-59 kcal/mol
Surface area17690 Å2
Unit cell
Length a, b, c (Å)131.959, 131.959, 155.340
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-608-

NA

21A-1122-

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 / 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, 507 molecules

#2: Chemical ChemComp-F05 / 1H-isoindol-3-amine


Mass: 132.163 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H8N2 / 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.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 493 / 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: 3.75 Å3/Da / Density % sol: 67.17 %
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 2M / Detector: PIXEL / Date: Dec 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.6→46.03 Å / Num. obs: 104195 / % possible obs: 99.3 % / Redundancy: 19.6 % / Biso Wilson estimate: 20.95 Å2 / CC1/2: 1 / Rrim(I) all: 0.143 / Net I/σ(I): 19.53
Reflection shellResolution: 1.6→1.7 Å / Mean I/σ(I) obs: 1.22 / Num. unique obs: 16567 / CC1/2: 0.652 / Rrim(I) all: 3.124 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487phasing
XDSVERSION Jan 10, 2022data reduction
XDSVERSION Jan 10, 2022data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jxh

5jxh


Resolution: 1.6→46.03 Å / SU ML: 0.1726 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.5972
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.179 5172 4.97 %
Rwork0.1659 98954 -
obs0.1665 104126 99.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.18 Å2
Refinement stepCycle: LAST / Resolution: 1.6→46.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3601 0 64 493 4158
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00784006
X-RAY DIFFRACTIONf_angle_d0.94745482
X-RAY DIFFRACTIONf_chiral_restr0.0579585
X-RAY DIFFRACTIONf_plane_restr0.009773
X-RAY DIFFRACTIONf_dihedral_angle_d12.97841472
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.620.34561690.31593258X-RAY DIFFRACTION98.7
1.62-1.640.32011580.29643216X-RAY DIFFRACTION98.83
1.64-1.660.29241730.29563254X-RAY DIFFRACTION98.93
1.66-1.680.29121730.27713217X-RAY DIFFRACTION99.01
1.68-1.70.30281960.25133220X-RAY DIFFRACTION98.93
1.7-1.720.26111780.24633223X-RAY DIFFRACTION98.92
1.72-1.750.22712080.22993215X-RAY DIFFRACTION99.13
1.75-1.770.23851460.21513278X-RAY DIFFRACTION99.36
1.77-1.80.23321640.23265X-RAY DIFFRACTION99.1
1.8-1.830.24092010.20073238X-RAY DIFFRACTION99.25
1.83-1.860.1851600.18983265X-RAY DIFFRACTION99.54
1.86-1.90.21071730.1943256X-RAY DIFFRACTION99.28
1.9-1.930.28421780.26183219X-RAY DIFFRACTION98.09
1.93-1.970.22081580.19053297X-RAY DIFFRACTION99.28
1.97-2.020.18581480.1753294X-RAY DIFFRACTION99.48
2.02-2.060.19171660.16543295X-RAY DIFFRACTION99.6
2.06-2.110.17881860.15733262X-RAY DIFFRACTION99.51
2.11-2.170.15591670.13553301X-RAY DIFFRACTION99.66
2.17-2.240.17961710.16593258X-RAY DIFFRACTION98.11
2.24-2.310.18891500.16273235X-RAY DIFFRACTION97.61
2.31-2.390.14971520.13343341X-RAY DIFFRACTION99.8
2.39-2.490.15661620.13683345X-RAY DIFFRACTION99.91
2.49-2.60.17211580.13933324X-RAY DIFFRACTION99.83
2.6-2.740.16291720.15133342X-RAY DIFFRACTION99.86
2.74-2.910.15671870.153332X-RAY DIFFRACTION100
2.91-3.130.16121610.14853383X-RAY DIFFRACTION100
3.13-3.450.17491970.15223359X-RAY DIFFRACTION100
3.45-3.950.13471760.13863386X-RAY DIFFRACTION99.53
3.95-4.970.13871850.12813454X-RAY DIFFRACTION100
4.97-46.030.18521990.19653622X-RAY DIFFRACTION99.48
Refinement TLS params.Method: refined / Origin x: 35.0518418637 Å / Origin y: -37.7766082404 Å / Origin z: 0.0144734453074 Å
111213212223313233
T0.148023429072 Å2-0.00298465884376 Å20.00211567389537 Å2-0.196014922445 Å20.00608822105888 Å2--0.185834655037 Å2
L0.311083951715 °20.0282832031243 °2-0.0893529586758 °2-0.498246079021 °20.251015981116 °2--0.575493869994 °2
S-0.000679967882155 Å °0.0221129823953 Å °-0.00767464692092 Å °-0.0461229602478 Å °-0.0055298374846 Å °0.048236857185 Å °-0.00659103755607 Å °-0.0954729975794 Å °-0.000342337686696 Å °
Refinement TLS groupSelection details: chain A

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