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- PDB-7lcu: X-ray structure of Furin bound to BOS-318, a small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 7lcu
TitleX-ray structure of Furin bound to BOS-318, a small molecule inhibitor
ComponentsFurin
KeywordsHYDROLASE/INHIBITOR / Inhibitor protease / HYDROLASE-INHIBITOR 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.24 Å
AuthorsCampobasso, N. / Reid, R.
Citation
Journal: Cell Chem Biol / Year: 2022
Title: A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease.
Authors: Douglas, L.E.J. / Reihill, J.A. / Ho, M.W.Y. / Axten, J.M. / Campobasso, N. / Schneck, J.L. / Rendina, A.R. / Wilcoxen, K.M. / Martin, S.L.
#1: Journal: Acta Crystallogr.,Sect.F / Year: 2019
Title: BacMam production and crystal structure of nonglycosylated apo human furin at 1.89 angstrom resolution.
Authors: Pearce, K.H. / Overton, L.K. / Gampe, R.T. / Barrett, G.B. / Taylor, J.D. / McKee, D.D. / Campobasso, N. / Nolte, R.T. / Reid, R.A.
History
DepositionJan 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Furin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,3688
Polymers53,5121
Non-polymers8567
Water6,341352
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area700 Å2
ΔGint-28 kcal/mol
Surface area17050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.994, 67.383, 88.632
Angle α, β, γ (deg.)90.000, 122.697, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-1017-

HOH

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Components

#1: Protein Furin / / Dibasic-processing enzyme / Paired basic amino acid residue-cleaving enzyme / PACE


Mass: 53511.602 Da / Num. of mol.: 1 / Fragment: UNP residues 108-574
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FURIN, FUR, PACE, PCSK3 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P09958, furin
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-XTA / (1-{[2-(3,5-dichlorophenyl)-6-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxy}pyridin-4-yl]methyl}piperidin-4-yl)acetic acid


Mass: 571.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32Cl2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 352 / Source method: isolated from a natural source / Formula: H2O
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: 2.25 Å3/Da / Density % sol: 45.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5 / Details: PEG8000, potassium dihydrogen phosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 4, 2016
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 1.24→48 Å / Num. obs: 131144 / % possible obs: 96 % / Redundancy: 2 % / Biso Wilson estimate: 10.3 Å2 / CC1/2: 0.99 / Net I/σ(I): 15.6
Reflection shellResolution: 1.24→1.28 Å / Num. unique obs: 13009 / CC1/2: 0.825 / % possible all: 96

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Processing

Software
NameVersionClassification
PHENIX1.19_4080refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4Z2A

4z2a


Resolution: 1.24→48 Å / SU ML: 0.1103 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.8426
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 + omega-cdl
RfactorNum. reflection% reflection
Rfree0.1944 6408 4.89 %
Rwork0.1764 124736 -
obs0.1773 131144 96.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 14.5 Å2
Refinement stepCycle: LAST / Resolution: 1.24→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3568 0 51 352 3971
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00443807
X-RAY DIFFRACTIONf_angle_d0.77865221
X-RAY DIFFRACTIONf_chiral_restr0.0814568
X-RAY DIFFRACTIONf_plane_restr0.0074692
X-RAY DIFFRACTIONf_dihedral_angle_d13.53291376
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.24-1.250.27511810.26684172X-RAY DIFFRACTION95.71
1.25-1.260.30062540.25494072X-RAY DIFFRACTION96.43
1.26-1.280.27981930.24184142X-RAY DIFFRACTION96.18
1.28-1.30.23742010.23994139X-RAY DIFFRACTION96.23
1.3-1.310.231760.23414181X-RAY DIFFRACTION97.06
1.31-1.330.242060.23254150X-RAY DIFFRACTION96.74
1.33-1.350.23562450.21784098X-RAY DIFFRACTION96.64
1.35-1.370.23442240.22044179X-RAY DIFFRACTION97.15
1.37-1.390.22662290.21594160X-RAY DIFFRACTION97.23
1.39-1.410.18862110.20774177X-RAY DIFFRACTION97.34
1.41-1.440.2172310.19744130X-RAY DIFFRACTION97.45
1.44-1.470.21342380.19184199X-RAY DIFFRACTION97.39
1.47-1.490.23191970.18824177X-RAY DIFFRACTION97.85
1.49-1.520.19352210.1874207X-RAY DIFFRACTION98.03
1.52-1.560.21761860.17914244X-RAY DIFFRACTION98.12
1.56-1.590.19592420.18344207X-RAY DIFFRACTION98.39
1.59-1.630.20432080.17354232X-RAY DIFFRACTION98.38
1.63-1.680.18382230.17534227X-RAY DIFFRACTION98.45
1.68-1.730.17172160.16474244X-RAY DIFFRACTION98.48
1.73-1.780.16761950.16564284X-RAY DIFFRACTION98.98
1.78-1.850.1791830.16674269X-RAY DIFFRACTION99.09
1.85-1.920.17812010.16563943X-RAY DIFFRACTION97.53
1.92-2.010.17892250.17163917X-RAY DIFFRACTION97.76
2.01-2.110.17681950.16813829X-RAY DIFFRACTION88.32
2.11-2.240.17672100.16194234X-RAY DIFFRACTION98.76
2.26-2.420.19082090.16943971X-RAY DIFFRACTION99.22
2.42-2.660.19662360.17754316X-RAY DIFFRACTION99.82
2.66-3.050.21552210.17464092X-RAY DIFFRACTION95.04
3.05-3.840.18232330.16554201X-RAY DIFFRACTION96.71
3.84-480.16562180.14614343X-RAY DIFFRACTION98.15

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