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

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Basic information

Entry
Database: PDB / ID: 7aqg
TitleCrystal Structure of Small Molecule Inhibitor TM5484 Bound to Stabilized Active Plasminogen Activator Inhibitor-1 (PAI-1-W175F)
Components
  • Plasminogen activator inhibitor 1
  • VHH-2g-42 (Nb42)
  • VHH-2w-64 (Nb64)
KeywordsHYDROLASE / plasminogen activator inhibitor-1 / PAI-1 / PAI-1-W175F / serpin / protease inhibitor / serine protease inhibitor / small molecule / antibody fragments / nanobodies / protein complex
Function / homology
Function and homology information


positive regulation of leukotriene production involved in inflammatory response / dentinogenesis / negative regulation of smooth muscle cell-matrix adhesion / peptidase inhibitor complex / positive regulation of coagulation / negative regulation of smooth muscle cell migration / Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition / negative regulation of vascular wound healing / negative regulation of wound healing / positive regulation of odontoblast differentiation ...positive regulation of leukotriene production involved in inflammatory response / dentinogenesis / negative regulation of smooth muscle cell-matrix adhesion / peptidase inhibitor complex / positive regulation of coagulation / negative regulation of smooth muscle cell migration / Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition / negative regulation of vascular wound healing / negative regulation of wound healing / positive regulation of odontoblast differentiation / negative regulation of cell adhesion mediated by integrin / regulation of signaling receptor activity / negative regulation of plasminogen activation / Dissolution of Fibrin Clot / positive regulation of monocyte chemotaxis / replicative senescence / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / ECM proteoglycans / negative regulation of endothelial cell apoptotic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / serine protease inhibitor complex / fibrinolysis / negative regulation of proteolysis / BMAL1:CLOCK,NPAS2 activates circadian expression / platelet alpha granule lumen / negative regulation of cell migration / positive regulation of interleukin-8 production / serine-type endopeptidase inhibitor activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / positive regulation of receptor-mediated endocytosis / positive regulation of angiogenesis / positive regulation of inflammatory response / Platelet degranulation / : / cellular response to lipopolysaccharide / protease binding / angiogenesis / 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 / Immunoglobulins ...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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-RV2 / Plasminogen activator inhibitor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Vicugna pacos (alpaca)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 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 24, 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
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Plasminogen activator inhibitor 1
B: VHH-2g-42 (Nb42)
C: VHH-2w-64 (Nb64)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0044
Polymers68,6203
Non-polymers3851
Water88349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2850 Å2
ΔGint-12 kcal/mol
Surface area24550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.511, 71.482, 96.210
Angle α, β, γ (deg.)90.000, 101.330, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 42780.031 Da / Num. of mol.: 1 / Mutation: W175F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SERPINE1, PAI1, PLANH1 / Plasmid: pETHSUK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Rosetta 2(DE3)pLysS / References: UniProt: P05121
#2: Antibody VHH-2g-42 (Nb42)


Mass: 12752.254 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Plasmid: pETHSUK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Rosetta 2(DE3)pLysS
#3: Antibody VHH-2w-64 (Nb64)


Mass: 13087.387 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Plasmid: pETHSUK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Rosetta 2(DE3)pLysS
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.24 Å3/Da / Density % sol: 45 % / Mosaicity: 0.21 °
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M BIS-TRIS, 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: 0.99187 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 1, 2017
RadiationMonochromator: Si (111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99187 Å / Relative weight: 1
ReflectionResolution: 2.13→94.34 Å / Num. obs: 33767 / % possible obs: 99.6 % / Redundancy: 3.7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.046 / Rrim(I) all: 0.09 / Net I/σ(I): 8.1 / Num. measured all: 124847 / 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
2.13-2.253.90.8751891649100.7710.5081.0151.499.8
6.74-94.343.40.041381611130.9970.0250.04820.499

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Processing

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

6gwn


Resolution: 2.27→43.8 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 31.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2677 2083 7.45 %
Rwork0.2148 25874 -
obs0.2187 27957 99.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 106.02 Å2 / Biso mean: 58.3645 Å2 / Biso min: 29.52 Å2
Refinement stepCycle: final / Resolution: 2.27→43.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4561 0 27 49 4637
Biso mean--56.09 49.95 -
Num. residues----597
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.27-2.320.361490.331916691818100
2.32-2.380.37921430.309617571900100
2.38-2.450.35331360.29116961832100
2.45-2.520.3861310.291117411872100
2.52-2.60.38091260.292617211847100
2.6-2.690.33281350.257117481883100
2.69-2.80.29541400.264316901830100
2.8-2.930.30391480.246617271875100
2.93-3.080.32211460.25491713185999
3.08-3.270.2761450.248817341879100
3.27-3.530.25551580.23211700185899
3.53-3.880.27521380.21031717185599
3.88-4.440.24121290.17391738186799
4.44-5.590.2191390.16851724186399
5.6-43.80.19511200.17361799191999

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