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- PDB-8oyh: X-ray structure of furin (PCSK3) in complex with Guanidinomethyl-... -

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Basic information

Entry
Database: PDB / ID: 8oyh
TitleX-ray structure of furin (PCSK3) in complex with Guanidinomethyl-Phac-Can-Tle-Can-6-(aminomethyl)-3-amino-isoindol
Components
  • Furin
  • Guanidinomethyl-Phac-Can-Tle-Can-6-(aminomethyl)-3-amino-isoindol
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 / 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 / Elastic fibre formation / heparan sulfate binding / blastocyst formation / 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 / amyloid fibril formation / Potential therapeutics for SARS / 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)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDahms, S.O. / Brandstetter, H.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science FundM2730 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
DepositionMay 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1May 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
B: Guanidinomethyl-Phac-Can-Tle-Can-6-(aminomethyl)-3-amino-isoindol
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,27411
Polymers52,8932
Non-polymers3819
Water6,125340
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2940 Å2
ΔGint-55 kcal/mol
Surface area17220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.245, 131.245, 154.618
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-1003-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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
#2: Protein/peptide Guanidinomethyl-Phac-Can-Tle-Can-6-(aminomethyl)-3-amino-isoindol


Mass: 780.901 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 349 molecules

#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 / Chloride


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


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 3.76 Å3/Da / Density % sol: 67.27 %
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: ESRF / Beamline: ID23-1 / Wavelength: 0.8856 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 1.8→45.79 Å / Num. obs: 72749 / % possible obs: 99.6 % / Redundancy: 6.7 % / Biso Wilson estimate: 29.58 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.103 / Net I/σ(I): 12.14
Reflection shellResolution: 1.8→1.91 Å / Mean I/σ(I) obs: 1.32 / Num. unique obs: 11526 / CC1/2: 0.68 / Rrim(I) all: 1.929 / % possible all: 99.2

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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 / Resolution: 1.8→40.53 Å / SU ML: 0.1852 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.7516
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.188 3569 4.92 %
Rwork0.1735 69038 -
obs0.1743 72607 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.56 Å2
Refinement stepCycle: LAST / Resolution: 1.8→40.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3597 0 71 340 4008
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063840
X-RAY DIFFRACTIONf_angle_d0.72595248
X-RAY DIFFRACTIONf_chiral_restr0.0497564
X-RAY DIFFRACTIONf_plane_restr0.0064703
X-RAY DIFFRACTIONf_dihedral_angle_d12.47551414
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.820.33511780.32332643X-RAY DIFFRACTION99.02
1.82-1.850.30911200.31122718X-RAY DIFFRACTION99.16
1.85-1.880.32471550.29092709X-RAY DIFFRACTION99.1
1.88-1.910.30971370.27472681X-RAY DIFFRACTION98.84
1.91-1.940.30031420.25662719X-RAY DIFFRACTION99.17
1.94-1.970.29861270.2392723X-RAY DIFFRACTION99.41
1.97-2.010.24131290.22682728X-RAY DIFFRACTION99
2.01-2.050.21641430.21282726X-RAY DIFFRACTION99.69
2.05-2.090.20221410.18872733X-RAY DIFFRACTION99.45
2.09-2.130.22681420.18522731X-RAY DIFFRACTION99.65
2.13-2.180.23761470.17962745X-RAY DIFFRACTION99.62
2.18-2.240.20591370.16732707X-RAY DIFFRACTION99.65
2.24-2.30.17841290.16612764X-RAY DIFFRACTION99.38
2.3-2.370.18031260.16412762X-RAY DIFFRACTION99.72
2.37-2.440.20651340.17052757X-RAY DIFFRACTION99.83
2.44-2.530.18431360.1652772X-RAY DIFFRACTION99.62
2.53-2.630.17421260.16742782X-RAY DIFFRACTION99.86
2.63-2.750.18841580.172745X-RAY DIFFRACTION99.79
2.75-2.90.21451480.17482783X-RAY DIFFRACTION99.93
2.9-3.080.18821440.17632787X-RAY DIFFRACTION100
3.08-3.320.19141520.16232787X-RAY DIFFRACTION99.8
3.32-3.650.15551570.14952805X-RAY DIFFRACTION99.93
3.65-4.180.1541460.1312840X-RAY DIFFRACTION99.8
4.18-5.260.12771550.1372868X-RAY DIFFRACTION99.74
5.26-40.530.19721600.20693023X-RAY DIFFRACTION99.07
Refinement TLS params.Method: refined / Origin x: 35.1571058113 Å / Origin y: -37.4270288921 Å / Origin z: 0.0628631941154 Å
111213212223313233
T0.231984368957 Å2-0.0164590608507 Å20.0111672731044 Å2-0.294901828936 Å20.00364796952676 Å2--0.2720080334 Å2
L0.521271077928 °20.119968616059 °2-0.000311319357044 °2-0.773066312249 °20.3496389658 °2--0.805820409422 °2
S-0.0235089248014 Å °0.0553895283192 Å °-0.0330076156985 Å °-0.0917144377772 Å °0.0170810859769 Å °0.0245900011593 Å °-0.00861032896151 Å °-0.102363112588 Å °-4.99904920823E-8 Å °
Refinement TLS groupSelection details: chain A

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