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- PDB-7aqf: Crystal Structure of Small Molecule Inhibitor TM5484 Bound to Sta... -

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Basic information

Entry
Database: PDB / ID: 7aqf
TitleCrystal Structure of Small Molecule Inhibitor TM5484 Bound to Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-stab)
ComponentsPlasminogen activator inhibitor 1
KeywordsHYDROLASE / plasminogen activator inhibitor-1 / PAI-1 / PAI-1-stab / serpin / protease inhibitor / serine protease inhibitor / small molecule inhibitor
Function / homology
Function and homology information


positive regulation of leukotriene production involved in inflammatory response / dentinogenesis / negative regulation of smooth muscle cell-matrix adhesion / negative regulation of smooth muscle cell migration / peptidase inhibitor complex / negative regulation of vascular wound healing / negative regulation of wound healing / positive regulation of odontoblast differentiation / negative regulation of cell adhesion mediated by integrin / negative regulation of endopeptidase activity ...positive regulation of leukotriene production involved in inflammatory response / dentinogenesis / negative regulation of smooth muscle cell-matrix adhesion / negative regulation of smooth muscle cell migration / peptidase inhibitor complex / negative regulation of vascular wound healing / negative regulation of wound healing / positive regulation of odontoblast differentiation / negative regulation of cell adhesion mediated by integrin / negative regulation of endopeptidase activity / regulation of signaling receptor activity / negative regulation of plasminogen activation / negative regulation of blood coagulation / positive regulation of monocyte chemotaxis / Dissolution of Fibrin Clot / replicative senescence / ECM proteoglycans / positive regulation of blood coagulation / negative regulation of fibrinolysis / negative regulation of endothelial cell apoptotic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / serine protease inhibitor complex / fibrinolysis / BMAL1:CLOCK,NPAS2 activates circadian gene expression / platelet alpha granule lumen / negative regulation of cell migration / positive regulation of interleukin-8 production / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / serine-type endopeptidase inhibitor activity / positive regulation of receptor-mediated endocytosis / positive regulation of inflammatory response / positive regulation of angiogenesis / Platelet degranulation / cellular response to lipopolysaccharide / protease binding / angiogenesis / collagen-containing extracellular matrix / defense response to Gram-negative bacterium / signaling receptor binding / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Serpin, conserved site / Serpins signature. / Serpin superfamily, domain 2 / Serpin family / Serpin domain / Serpin superfamily / Serpin superfamily, domain 1 / Serpin (serine protease inhibitor) / SERine Proteinase INhibitors
Similarity search - Domain/homology
Chem-RV2 / Plasminogen activator inhibitor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 Å
AuthorsSillen, M. / Strelkov, S.V. / Declerck, P.J.
Funding support Belgium, 2items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)11ZQ918N Belgium
Research Foundation - Flanders (FWO)G072915N Belgium
CitationJournal: Int J Mol Sci / Year: 2021
Title: Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.
Authors: Sillen, M. / Miyata, T. / Vaughan, D.E. / Strelkov, S.V. / Declerck, P.J.
History
DepositionOct 21, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Plasminogen activator inhibitor 1
B: Plasminogen activator inhibitor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,8873
Polymers85,5022
Non-polymers3851
Water8,665481
1
A: Plasminogen activator inhibitor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1362
Polymers42,7511
Non-polymers3851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Plasminogen activator inhibitor 1


Theoretical massNumber of molelcules
Total (without water)42,7511
Polymers42,7511
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.296, 64.322, 106.644
Angle α, β, γ (deg.)90.000, 116.960, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Plasminogen activator inhibitor 1 / PAI-1 / Endothelial plasminogen activator inhibitor / Serpin E1


Mass: 42751.008 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SERPINE1, PAI1, PLANH1 / Plasmid: pETHSUK / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Rosetta 2(DE3)pLysS / References: UniProt: P05121
#2: Chemical ChemComp-RV2 / 5-Chloro-2-[[2-[3-(furan-3-yl)anilino]-2-oxoacetyl]amino]benzoic acid / 5-chloranyl-2-[[2-[[3-(furan-3-yl)phenyl]amino]-2-oxidanylidene-ethanoyl]amino]benzoic acid / TM5484 / CHEMBL4210355


Mass: 384.770 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H13ClN2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 481 / 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: 2.42 Å3/Da / Density % sol: 49.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.3 / Details: 0.2 M TRISODIUM CITRATE, 10% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97856 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 18, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.73→66.3 Å / Num. obs: 85314 / % possible obs: 99.5 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.038 / Rrim(I) all: 0.099 / Net I/σ(I): 8.5 / Num. measured all: 576610 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.73-1.8271.20885847123450.750.4891.3051.798.9
5.46-66.36.10.0391727928130.9990.0170.04319.599.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GWP

6gwp


Resolution: 1.77→33.44 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2135 3996 5.04 %
Rwork0.1783 75248 -
obs0.1801 79244 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 80.62 Å2 / Biso mean: 30.1522 Å2 / Biso min: 14.62 Å2
Refinement stepCycle: final / Resolution: 1.77→33.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5746 0 39 481 6266
Biso mean--35.38 39.73 -
Num. residues----736
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 29

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.77-1.790.37311420.29712580272299
1.79-1.810.30691450.27622529267499
1.81-1.840.31231360.26212603273999
1.84-1.860.33131150.25142556267199
1.86-1.890.27011520.23022575272799
1.89-1.910.28661320.21442542267499
1.91-1.940.25571440.21632593273799
1.94-1.970.27321510.2042572272399
1.97-20.27061430.1982567271099
2-2.040.24711490.19242554270399
2.04-2.070.26051260.18682634276099
2.07-2.110.20451430.18692539268299
2.11-2.160.23681160.17222596271299
2.16-2.20.21941510.169725802731100
2.2-2.260.2071390.17112590272999
2.26-2.310.23611480.172572272099
2.31-2.380.22621390.182525962735100
2.38-2.440.27121250.185326012726100
2.45-2.520.2491400.18125812721100
2.52-2.610.23051340.183226222756100
2.61-2.720.20741290.179125962725100
2.72-2.840.20231330.180626112744100
2.84-2.990.23141520.189426022754100
2.99-3.180.21841360.187726172753100
3.18-3.420.20141310.178726452776100
3.42-3.770.20941350.16126222757100
3.77-4.310.18281290.146426312760100
4.31-5.430.15531390.147826512790100
5.43-33.440.16541420.17822691283399

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