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- PDB-8b4x: X-ray structure of furin (PCSK3) in complex with Guanidinomethyl-... -

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Basic information

Entry
Database: PDB / ID: 8b4x
TitleX-ray structure of furin (PCSK3) in complex with Guanidinomethyl-Phac-R-Tle-K-6-(aminomethyl)-3-amino-isoindol
Components
  • Furin
  • Guanidinomethyl-Phac-R-Tle-K-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 / 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)
synthetic construct (others)
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
B: Guanidinomethyl-Phac-R-Tle-K-6-(aminomethyl)-3-amino-isoindol
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,26712
Polymers52,8632
Non-polymers40410
Water8,197455
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2300 Å2
ΔGint-58 kcal/mol
Surface area17630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)132.049, 132.049, 155.492
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-607-

NA

31A-1081-

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-R-Tle-K-6-(aminomethyl)-3-amino-isoindol


Mass: 750.957 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 465 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.: 4 / 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.: 455 / 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: 67.24 %
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: ID30B / Wavelength: 0.968626 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 27, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.968626 Å / Relative weight: 1
ReflectionResolution: 1.6→46.06 Å / Num. obs: 104100 / % possible obs: 99 % / Redundancy: 19 % / Biso Wilson estimate: 23.44 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.153 / Net I/σ(I): 13.81
Reflection shellResolution: 1.6→1.7 Å / Mean I/σ(I) obs: 1.22 / Num. unique obs: 16441 / CC1/2: 0.513 / Rrim(I) all: 3.276 / % possible all: 98.1

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487phasing
XDSVERSION Jan 31, 2020data reduction
XDSVERSION Jan 31, 2020data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jxh

5jxh


Resolution: 1.6→46.06 Å / SU ML: 0.1922 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 17.7426
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1695 5165 4.96 %
Rwork0.158 98887 -
obs0.1585 104052 98.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.95 Å2
Refinement stepCycle: LAST / Resolution: 1.6→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3608 0 70 455 4133
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00753904
X-RAY DIFFRACTIONf_angle_d0.9685338
X-RAY DIFFRACTIONf_chiral_restr0.0548576
X-RAY DIFFRACTIONf_plane_restr0.0092713
X-RAY DIFFRACTIONf_dihedral_angle_d12.26511445
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.620.34341630.32853231X-RAY DIFFRACTION98.04
1.62-1.640.35161630.3173209X-RAY DIFFRACTION97.85
1.64-1.660.31221730.30493236X-RAY DIFFRACTION98.13
1.66-1.680.30221710.28543187X-RAY DIFFRACTION98.24
1.68-1.70.27921870.27183222X-RAY DIFFRACTION98.3
1.7-1.720.2461770.26113215X-RAY DIFFRACTION98.35
1.72-1.750.25722050.24523187X-RAY DIFFRACTION98.18
1.75-1.770.24781460.22663270X-RAY DIFFRACTION98.53
1.77-1.80.22961680.21023247X-RAY DIFFRACTION98.53
1.8-1.830.21681960.20273213X-RAY DIFFRACTION98.61
1.83-1.860.2181570.19313252X-RAY DIFFRACTION98.61
1.86-1.90.22941760.18383247X-RAY DIFFRACTION98.62
1.9-1.930.19331770.17653254X-RAY DIFFRACTION98.88
1.93-1.970.19511630.16343281X-RAY DIFFRACTION98.85
1.97-2.020.17671470.16063284X-RAY DIFFRACTION98.88
2.02-2.060.19321700.15313304X-RAY DIFFRACTION99.2
2.06-2.110.15571770.14183235X-RAY DIFFRACTION99.04
2.11-2.170.14951750.13123301X-RAY DIFFRACTION99.12
2.17-2.240.14381710.12823280X-RAY DIFFRACTION99.08
2.24-2.310.15231490.12673307X-RAY DIFFRACTION99.14
2.31-2.390.15791560.12813325X-RAY DIFFRACTION99.32
2.39-2.490.14121630.13663333X-RAY DIFFRACTION99.52
2.49-2.60.16071580.14163341X-RAY DIFFRACTION99.52
2.6-2.740.17251700.15593335X-RAY DIFFRACTION99.66
2.74-2.910.18531860.16073323X-RAY DIFFRACTION99.72
2.91-3.130.16361640.1573395X-RAY DIFFRACTION99.8
3.13-3.450.15711950.14473362X-RAY DIFFRACTION99.89
3.45-3.940.12711770.1263416X-RAY DIFFRACTION99.97
3.95-4.970.12251860.11873455X-RAY DIFFRACTION100
4.97-46.060.17871990.19043640X-RAY DIFFRACTION99.74
Refinement TLS params.Method: refined / Origin x: 35.3403029172 Å / Origin y: -37.8053366253 Å / Origin z: 0.128744691874 Å
111213212223313233
T0.170693660422 Å2-0.00831296121248 Å20.00742311605447 Å2-0.214050241005 Å2-0.00111421937122 Å2--0.208006922052 Å2
L0.420080119593 °20.0983947186962 °2-0.0711591920779 °2-0.55660905735 °20.260583656134 °2--0.758502189001 °2
S-0.0128032760368 Å °0.0461037434492 Å °-0.0272691968828 Å °-0.0593369118908 Å °0.00961796114022 Å °0.0228719477898 Å °-0.00804550316426 Å °-0.0764836236194 Å °-4.31170865434E-6 Å °
Refinement TLS groupSelection details: chain A

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