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- PDB-1gj9: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER19... -

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Basic information

Entry
Database: PDB / ID: 1gj9
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 / serine-type endopeptidase complex ...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 / serine-type endopeptidase complex / regulation of smooth muscle cell migration / 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / 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
Chem-134 / CITRIC ACID / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.8 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 30, 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 1.4Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_special_symmetry / 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 1.5Nov 20, 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)31,9095
Polymers31,1442
Non-polymers7663
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2310 Å2
ΔGint-2 kcal/mol
Surface area11420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.61, 50.37, 65.92
Angle α, β, γ (deg.)90.0, 113.04, 90.0
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-442-

HOH

21B-515-

HOH

31B-551-

HOH

41B-551-

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-134 / 6-FLUORO-2-[2-HYDROXY-3-(2-METHYL-CYCLOHEXYLOXY)-PHENYL]-1H-INDOLE-5-CARBOXAMIDINE


Mass: 381.443 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24FN3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / 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 Å3/Da / Density % sol: 38.52 %
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: Mar 19, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.45→27.58 Å / Num. all: 44131 / Num. obs: 17859 / % possible obs: 40.5 % / Observed criterion σ(I): 0.9 / Redundancy: 1.7 % / Rmerge(I) obs: 0.079 / Net I/σ(I): 4.8
Reflection shellResolution: 1.77→1.85 Å / Rmerge(I) obs: 0.221 / Num. unique all: 1058 / % possible all: 29.3
Reflection
*PLUS
Num. obs: 14468
Reflection shell
*PLUS
Highest resolution: 1.8 Å / Lowest resolution: 1.88 Å

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Processing

Software
NameVersionClassification
bioteXdata collection
bioteXdata reduction
X-PLOR3.851refinement
bioteXdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.8→7 Å / Cross valid method: THROUGHOUT / σ(F): 1.85 / Stereochemistry target values: X-PLOR force field
Details: Only Leu_A9 to Lys_A16 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 Leu_A9 to Lys_A16 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: Lys_A10, Ile_B16, Glu_B25, Met_B47, Glu_B84, Glu_B86, Thr_B139, Gln_B192, Leu_B209, Pro_B225, Leu_B235, BMZ_246 (inhibitor) Disordered waters are: HOH119 which is close to a symmetry-related equivalent of itself; HOH373 which is close to HOH374; HOH600 which is close to a symmetry-related equivalent of itself; HOH602 which is close to HOH603; HOH951 which is close to a symmetry-related equivalent of itself; HOH1022 which is close to a symmetry-related equivalent of itself; No energy terms between citrate 1 and 2 are included because they are hydrogen-bonded to one another via unusually short hydrogen bonds between carboxylate / hydroxyl groups.
RfactorNum. reflection% reflection
Rfree0.222 2635 10 %
Rwork0.178 --
obs0.181 14468 64.1 %
all-22571 -
Refinement stepCycle: LAST / Resolution: 1.8→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2019 0 54 320 2393
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.017
X-RAY DIFFRACTIONx_angle_deg4.1
Refinement
*PLUS
Highest resolution: 2 Å / % reflection Rfree: 10 % / Rfactor all: 0.181 / Rfactor obs: 0.166 / Rfactor Rwork: 0.166
Solvent computation
*PLUS
Displacement parameters
*PLUS
LS refinement shell
*PLUS
Highest resolution: 1.8 Å / Lowest resolution: 1.88 Å / Rfactor Rwork: 0.181 / Rfactor obs: 0.181

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