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- PDB-2viv: Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioa... -

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Basic information

Entry
Database: PDB / ID: 2viv
TitleFragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator
ComponentsUROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B
KeywordsHYDROLASE / PLASMINOGEN ACTIVATION / EGF-LIKE DOMAIN / BLOOD COAGULATION / INHIBITOR / POLYMORPHISM / GLYCOPROTEIN / FIBRINOLYSIS / KRINGLE / ZYMOGEN / SECRETED / PROTEASE / UROKINASE-TYPE PLASMINOGEN ACTIVATOR / PHARMACEUTICAL / SERINE PROTEASE / PHOSPHORYLATION
Function / homology
Function and homology information


u-plasminogen activator / regulation of smooth muscle cell-matrix adhesion / urokinase plasminogen activator signaling pathway / regulation of plasminogen activation / regulation of fibrinolysis / regulation of wound healing / protein complex involved in cell-matrix adhesion / negative regulation of plasminogen activation / regulation of smooth muscle cell migration / regulation of signaling receptor activity ...u-plasminogen activator / regulation of smooth muscle cell-matrix adhesion / urokinase plasminogen activator signaling pathway / regulation of plasminogen activation / regulation of fibrinolysis / regulation of wound healing / protein complex involved in cell-matrix adhesion / negative regulation of plasminogen activation / regulation of smooth muscle cell migration / regulation of signaling receptor activity / serine-type endopeptidase complex / Dissolution of Fibrin Clot / smooth muscle cell migration / plasminogen activation / tertiary granule membrane / regulation of cell adhesion mediated by integrin / negative regulation of fibrinolysis / specific granule membrane / regulation of cell adhesion / serine protease inhibitor complex / fibrinolysis / chemotaxis / blood coagulation / regulation of cell population proliferation / response to hypoxia / positive regulation of cell migration / external side of plasma membrane / serine-type endopeptidase activity / focal adhesion / Neutrophil degranulation / cell surface / signal transduction / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / EGF-like domain profile. / EGF-like domain signature 1. ...Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / EGF-like domain profile. / EGF-like domain signature 1. / EGF-like domain / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
ACETATE ION / Chem-VG2 / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.72 Å
AuthorsFrederickson, M. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S.R. / Matthews, J.E. / McMenamin, R. / Smith, D. / Vinkovic, M. / Wallis, N.G.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator.
Authors: Frederickson, M. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S.R. / Matthews, J.E. / Mcmenamin, R. / Smith, D. / Vinkovic, M. / Wallis, N.G.
History
DepositionDec 5, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2008Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: UROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,9053
Polymers28,4441
Non-polymers4612
Water4,035224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)52.338, 54.001, 81.938
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein UROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B / UROKINASE-TYPE PLASMINOGEN ACTIVATOR / UPA / U-PLASMINOGEN ACTIVATOR


Mass: 28444.346 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 179-431 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00749, u-plasminogen activator
#2: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-VG2 / 4-(2-aminoethoxy)-N-(3-chloro-5-piperidin-1-ylphenyl)-3,5-dimethylbenzamide


Mass: 401.930 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H28ClN3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, MET 214 TO ILE ENGINEERED RESIDUE IN CHAIN A, CYS 299 TO SER

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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: 1.86 Å3/Da / Density % sol: 39.54 % / Description: NONE
Crystal growpH: 6.6
Details: PROTEIN WAS CRYSTALLIZED FROM 22-24% PEG4000, 0.17M (NH4)2SO4, 15% GLYCEROL, 0.1M NA(CH3COO) PH=4.0; THEN SOAKED IN 0.04M COMPOUND, 28% PEG4000, 5% GLYCEROL, 0.29M BISTRIS PH=6.6, 0.001M ...Details: PROTEIN WAS CRYSTALLIZED FROM 22-24% PEG4000, 0.17M (NH4)2SO4, 15% GLYCEROL, 0.1M NA(CH3COO) PH=4.0; THEN SOAKED IN 0.04M COMPOUND, 28% PEG4000, 5% GLYCEROL, 0.29M BISTRIS PH=6.6, 0.001M NA(CH3COO), 0.001M (NH4)2SO4

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Details: OSMIC BLUE CONFOCAL OPTICS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.72→34.16 Å / Num. obs: 21002 / % possible obs: 82.8 % / Observed criterion σ(I): 0 / Redundancy: 2.4 % / Rmerge(I) obs: 0.06
Reflection shellResolution: 1.72→1.73 Å / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 2 / % possible all: 22.6

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Processing

Software
NameVersionClassification
BUSTER-TNT2.1.1refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.72→34.16 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2377 1044 5 %RANDOM
Rwork0.1801 ---
obs0.183 21002 82.75 %-
Refinement stepCycle: LAST / Resolution: 1.72→34.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1952 0 32 224 2208

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