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- PDB-1gja: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER19... -

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Basic information

Entry
Database: PDB / ID: 1gja
TitleENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS
Components(UROKINASE-TYPE PLASMINOGEN ACTIVATOR) x 2
KeywordsBLOOD CLOTTING / hydrolase / selectivity at S1 / H2O displacement / uPA / tPA / Ser190/Ala190 protease / structure-based drug design
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 / regulation of signaling receptor activity / negative regulation of plasminogen activation / regulation of smooth muscle cell migration ...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 / regulation of signaling receptor activity / negative regulation of plasminogen activation / regulation of smooth muscle cell migration / serine-type endopeptidase complex / Dissolution of Fibrin Clot / smooth muscle cell migration / plasminogen activation / regulation of cell adhesion mediated by integrin / tertiary granule membrane / negative regulation of fibrinolysis / regulation of cell adhesion / specific granule membrane / 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. ...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 family, serine active site. / Serine proteases, trypsin domain profile. / 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
N-(4-CARBAMIMIDOYL-PHENYL)-2-HYDROXY-BENZAMIDE / CITRIC ACID / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.56 Å
AuthorsKatz, B.A. / Sprengeler, P.A. / Luong, C. / Verner, E. / Spencer, J.R. / Breitenbucher, J.G. / Hui, H. / McGee, D. / Allen, D. / Martelli, A. / Mackman, R.L.
CitationJournal: Chem.Biol. / Year: 2001
Title: Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets.
Authors: Katz, B.A. / Sprengeler, P.A. / Luong, C. / Verner, E. / Elrod, K. / Kirtley, M. / Janc, J. / Spencer, J.R. / Breitenbucher, J.G. / Hui, H. / McGee, D. / Allen, D. / Martelli, A. / Mackman, R.L.
History
DepositionApr 27, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Version format compliance
Revision 1.3Oct 4, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Oct 11, 2017Group: Data collection / Category: reflns / Item: _reflns.percent_possible_obs
Revision 1.5Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,7835
Polymers31,1442
Non-polymers6403
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-4 kcal/mol
Surface area11680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.84, 50.26, 66.38
Angle α, β, γ (deg.)90.0, 113.13, 90.0
Int Tables number5
Cell settingmonoclinic
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-475-

HOH

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Components

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


Mass: 2708.183 Da / Num. of mol.: 1 / Fragment: SHORT CHAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: P.PASTORIS / Plasmid: PPIC9LMWUPA / Production host: Escherichia coli (E. coli) / References: UniProt: P00749
#2: Protein UROKINASE-TYPE PLASMINOGEN ACTIVATOR / E.C.3.4.21.73 / UPA / U-PLASMINOGEN ACTIVATOR / UROKINASE-PLASMINOGEN ACTIVATOR


Mass: 28435.428 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN / Mutation: N145A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: P.PASTORIS / Plasmid: PPIC9LMWUPA / Production host: Escherichia coli (E. coli) / References: UniProt: P00749, u-plasminogen activator
#3: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#4: Chemical ChemComp-135 / N-(4-CARBAMIMIDOYL-PHENYL)-2-HYDROXY-BENZAMIDE


Mass: 255.272 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / Source method: isolated from a natural source / Formula: H2O
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: 2.01 Å3/Da / Density % sol: 38.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5
Details: 2-propanol PEG 4000, pH 6.5, vapor diffusion at 298 K, pH 6.50
Crystal grow
*PLUS
pH: 7.4 / Method: vapor diffusion, hanging drop / Details: Katz, B.A., (2000) Chem.Biol., 7, 299.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
10.28 mMprotein1drop
21.4 mMinhibitor1drop
320 %2-propanol1reservoir
420 %PEG40001reservoir
5100 mMsodium citrate1reservoir

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Aug 24, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.41→41.8 Å / Num. all: 48181 / Num. obs: 27315 / Observed criterion σ(I): 1 / Redundancy: 2.2 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 13.4
Reflection shellResolution: 1.6→1.75 Å / Rmerge(I) obs: 0.26 / Num. unique all: 3808 / % possible all: 49.2
Reflection
*PLUS
Num. obs: 25786
Reflection shell
*PLUS
Highest resolution: 1.56 Å / Lowest resolution: 1.63 Å

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Processing

Software
NameVersionClassification
bioteXdata collection
bioteXdata reduction
X-PLOR3.851refinement
bioteXdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.56→7 Å / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: X-PLOR force field
Details: Only Pro_A5 to Thr_A17 are included for the A-chain. Residues prior and after these residues are not visible (disordered). Residues after Lys_B243 are not visible (disordered). Residues ...Details: Only Pro_A5 to Thr_A17 are included for the A-chain. Residues prior and after these residues are not visible (disordered). Residues after Lys_B243 are not visible (disordered). Residues simultaneously refined in two or more conformations are: Met_B47, Met_B81, Ser_B95, Glu_B110B, Leu_B235 Disordered waters are: HOH7 which is close to HOH8 HOH432 which is close to HOH433 HOH588 which is close to HOH589 HOH704 which is close to HOH705 HOH838 which is close to HOH839 HOH780 which is close to HOH781 HOH1081 which is close to HOH1082 HOH1135 which is close to a symmetry-related equivalent of itself; HOH1119 which is close to HOH1120 No energy terms between citrate 1 and 2 are included because they are hydrogen-bonded to one another via an unusually short hydrogen bond between carboxylate / hydroxyl groups.
RfactorNum. reflection% reflection
Rfree0.209 2576 10 %
Rwork0.186 --
obs0.187 25786 73.62 %
all-35026 -
Refinement stepCycle: LAST / Resolution: 1.56→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2034 0 45 249 2328
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.015
X-RAY DIFFRACTIONx_angle_deg3.5
Refinement
*PLUS
Highest resolution: 2 Å / % reflection Rfree: 10 % / Rfactor all: 0.187 / Rfactor obs: 0.159 / Rfactor Rwork: 0.159
Solvent computation
*PLUS
Displacement parameters
*PLUS
LS refinement shell
*PLUS
Highest resolution: 1.56 Å / Lowest resolution: 1.63 Å / Rfactor Rwork: 0.187 / Rfactor obs: 0.187

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