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- PDB-8b4v: X-ray structure of furin (PCSK3) in complex with benzamidine -

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Basic information

Entry
Database: PDB / ID: 8b4v
TitleX-ray structure of furin (PCSK3) in complex with benzamidine
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 / Assembly of active LPL and LIPC lipase complexes / negative regulation of transforming growth factor beta1 production / signal peptide processing / regulation of cholesterol transport / negative regulation of low-density lipoprotein particle receptor catabolic 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 / negative regulation of low-density lipoprotein particle receptor catabolic process / peptide biosynthetic 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 / Elastic fibre formation / heparan sulfate binding / Signaling by NODAL / blastocyst formation / regulation of endopeptidase activity / peptide hormone processing / positive regulation of membrane protein ectodomain proteolysis / zymogen activation / CD163 mediating an anti-inflammatory response / regulation of protein catabolic process / Activation of Matrix Metalloproteinases / Maturation of hRSV A proteins / TGF-beta receptor signaling activates SMADs / Respiratory syncytial virus (RSV) attachment and entry / Uptake and function of anthrax toxins / Collagen degradation / protein maturation / collagen catabolic process / extracellular matrix disassembly / regulation of signal transduction / Removal of aminoterminal propeptides from gamma-carboxylated proteins / viral life cycle / serine-type peptidase activity / extracellular matrix organization / transforming growth factor beta receptor signaling pathway / negative regulation of inflammatory response to antigenic stimulus / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / peptide binding / trans-Golgi network / serine-type endopeptidase inhibitor activity / 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 / 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 / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / 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: 1.6 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

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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)52,95513
Polymers52,1121
Non-polymers84212
Water9,062503
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-48 kcal/mol
Surface area17760 Å2
Unit cell
Length a, b, c (Å)131.952, 131.952, 155.351
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-607-

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 / 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, 514 molecules

#2: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2 / 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.: 3 / 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.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 503 / 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: 3.75 Å3/Da / Density % sol: 67.16 %
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: Oct 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.6→47.17 Å / Num. obs: 104948 / % possible obs: 99.9 % / Redundancy: 19.7 % / Biso Wilson estimate: 20.89 Å2 / CC1/2: 1 / Rrim(I) all: 0.104 / Net I/σ(I): 22.94
Reflection shellResolution: 1.6→1.7 Å / Mean I/σ(I) obs: 2.05 / Num. unique obs: 16663 / CC1/2: 0.794 / Rrim(I) all: 1.636 / % possible all: 99.6

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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: 5jxh

5jxh


Resolution: 1.6→36.77 Å / SU ML: 0.1285 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 15.5526
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1658 5203 4.96 %
Rwork0.1535 99601 -
obs0.1541 104804 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.89 Å2
Refinement stepCycle: LAST / Resolution: 1.6→36.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3601 0 47 503 4151
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00623883
X-RAY DIFFRACTIONf_angle_d0.97515311
X-RAY DIFFRACTIONf_chiral_restr0.0546576
X-RAY DIFFRACTIONf_plane_restr0.0061713
X-RAY DIFFRACTIONf_dihedral_angle_d27.34141392
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.620.27941720.25683300X-RAY DIFFRACTION99.88
1.62-1.640.2451580.243254X-RAY DIFFRACTION99.91
1.64-1.660.28371750.23553282X-RAY DIFFRACTION99.91
1.66-1.680.25421740.22023248X-RAY DIFFRACTION99.94
1.68-1.70.24851960.20393255X-RAY DIFFRACTION99.94
1.7-1.720.21051830.19823258X-RAY DIFFRACTION100
1.72-1.750.18962070.18473246X-RAY DIFFRACTION100
1.75-1.770.20021470.1723296X-RAY DIFFRACTION99.94
1.77-1.80.18821650.16463295X-RAY DIFFRACTION99.97
1.8-1.830.17812020.16463263X-RAY DIFFRACTION99.97
1.83-1.860.18191610.16393279X-RAY DIFFRACTION100
1.86-1.90.17831730.16223286X-RAY DIFFRACTION100
1.9-1.930.18321840.15363267X-RAY DIFFRACTION99.86
1.93-1.970.18931580.14483321X-RAY DIFFRACTION100
1.97-2.020.15111490.14033309X-RAY DIFFRACTION100
2.02-2.060.16331660.13493313X-RAY DIFFRACTION100
2.06-2.110.13911890.13373274X-RAY DIFFRACTION99.94
2.11-2.170.1541670.13333313X-RAY DIFFRACTION99.97
2.17-2.240.15221760.12793314X-RAY DIFFRACTION99.97
2.24-2.310.1481530.13133319X-RAY DIFFRACTION99.97
2.31-2.390.13971510.13373347X-RAY DIFFRACTION100
2.39-2.490.15711630.14183344X-RAY DIFFRACTION100
2.49-2.60.16051580.14533333X-RAY DIFFRACTION100
2.6-2.740.15121720.15143347X-RAY DIFFRACTION100
2.74-2.910.17691870.15863332X-RAY DIFFRACTION100
2.91-3.130.1681610.15673383X-RAY DIFFRACTION100
3.13-3.450.15921970.14923361X-RAY DIFFRACTION100
3.45-3.940.13471760.13963399X-RAY DIFFRACTION99.97
3.94-4.970.1411850.13173455X-RAY DIFFRACTION100
4.97-36.770.19221980.19133608X-RAY DIFFRACTION99.19
Refinement TLS params.Method: refined / Origin x: 35.032674652 Å / Origin y: -37.7195485717 Å / Origin z: 0.129393391756 Å
111213212223313233
T0.132326858862 Å20.00176841097352 Å20.00231169017409 Å2-0.173123911369 Å20.00796847029526 Å2--0.164558221846 Å2
L0.337252709551 °20.0297089196592 °2-0.0832750702214 °2-0.556189409211 °20.217967763496 °2--0.573770855531 °2
S-0.00526361931369 Å °0.0229914948659 Å °-0.00113135190661 Å °-0.0585521353523 Å °-0.00164452357411 Å °0.0477858376028 Å °-0.00779936996459 Å °-0.0882228851741 Å °9.26721961161E-6 Å °
Refinement TLS groupSelection details: chain A

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