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- PDB-1c5y: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,... -

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Basic information

Entry
Database: PDB / ID: 1c5y
TitleSTRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
Components(PROTEIN (UROKINASE-TYPE PLASMINOGEN ACTIVATOR)) x 2
KeywordsBLOOD CLOTTING / selective / S1 site inhibitor / structure-based drug design / urokinase / trypsin / thrombin
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
THIENO[2,3-B]PYRIDINE-2-CARBOXAMIDINE / CITRATE ANION / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 1.65 Å
AuthorsKatz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L.
CitationJournal: Chem.Biol. / Year: 2000
Title: Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator.
Authors: Katz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L.
History
DepositionDec 22, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 4, 2017Group: Advisory / Refinement description
Category: pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / software
Revision 1.4Dec 27, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / 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 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 1.6Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,8896
Polymers31,1442
Non-polymers7464
Water6,287349
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2220 Å2
ΔGint-3 kcal/mol
Surface area11630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.070, 49.570, 66.320
Angle α, β, γ (deg.)90.00, 113.20, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-273-

HOH

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Components

#1: Protein/peptide PROTEIN (UROKINASE-TYPE 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) / Plasmid: PPIC9 / Production host: Pichia pastoris (fungus) / Strain (production host): HISTIDINE DEFICIENT GS115 / References: UniProt: P00749, u-plasminogen activator
#2: Protein PROTEIN (UROKINASE-TYPE PLASMINOGEN ACTIVATOR)


Mass: 28435.428 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PPIC9 / Production host: Pichia pastoris (fungus) / Strain (production host): HISTIDINE DEFICIENT GS115 / References: UniProt: P00749, u-plasminogen activator
#3: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H5O7
#4: Chemical ChemComp-ESP / THIENO[2,3-B]PYRIDINE-2-CARBOXAMIDINE


Mass: 178.234 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H8N3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 1.99 Å3/Da / Density % sol: 25.6 %
Crystal growpH: 6.5
Details: LMW human uPA/A145 was concentrated to 10 mg/ml and incubated in 50 mM HEPES, 5.0 mM NaCl. pH 7.0, 5.0 mM thieno[2,3-b]pyridine-2-carboxamidine for 15 min on ice. The complex was ...Details: LMW human uPA/A145 was concentrated to 10 mg/ml and incubated in 50 mM HEPES, 5.0 mM NaCl. pH 7.0, 5.0 mM thieno[2,3-b]pyridine-2-carboxamidine for 15 min on ice. The complex was crystallized by vapor diffusion in hanging drops containing equal volumes of protein-inhibitor solution (0.28 mM uPA/A145, 1.4 mM inhibitor and well solution (20 % 2-propanol, 20 % PEG 4K, 100 mM sodium citrate, pH 6.5) sealed over the well.
Crystal grow
*PLUS
pH: 7.4 / Method: vapor diffusion, hanging drop
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 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 28, 1999 / Details: MSC MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.44→31.26 Å / Num. all: 23222 / % possible obs: 68 % / Observed criterion σ(I): 0.8 / Redundancy: 1.8 % / Rmerge(I) obs: 0.087 / Net I/σ(I): 7.2
Reflection shellResolution: 1.65→1.72 Å / Rmerge(I) obs: 0.255 / Mean I/σ(I) obs: 1.5 / % possible all: 32.1

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Processing

Software
NameVersionClassification
bioteX(MSC)data collection
bioteX(MSC)data reduction
X-PLOR3.1model building
Quantamodel building
Insight IImodel building
X-PLOR3.1refinement
bioteXdata scaling
X-PLOR3.1phasing
RefinementMethod to determine structure: DIFFERENCE FOURIER PLUS REFINEMENT
Starting model: PDB1LMW

Resolution: 1.65→7.5 Å / Cross valid method: X-PLOR / σ(F): 1.9
Details: Bulk solvent terms included in Fob file created with standard X-PLOR script. Only Leu A9 to Thr_A17 are included for the A-chain. Residues prior and after these residues are not visible ...Details: Bulk solvent terms included in Fob file created with standard X-PLOR script. Only Leu A9 to Thr_A17 are included for the A-chain. Residues prior and after these residues are not visible (disordered). Residues after Glu_B245 are not visible (disordered). Density for Lys_B243 through Glu_B245 is weak or absent Residues simultaneously refined in two or more conformations are: Ile_B17, Met_B47, Met_B81, Glu_B84, Glu_B86, Leu_B123, Thr_B139, Arg_B166, Gln_B192, Ser_B232, Leu_B235, the inhibitor (246). No energy terms between citrate 1 and 2 are included because they appear to be hydrogen-bonded to one another via an unusually short hydrogen bond between carboxylate groups. Disordered waters are: HOH75 which is close to HOH76; HOH247 which is close to a symmetry-related equivalent of HOH248 which in turn is close to HOH249; HOH104 which is close to HOH105; HOH155 which is close to conformation 1 of Glu_B84; HOH292 which is close to HOH298; HOH373 which is close to HOH374; HOH715 which is close to HOH720 which in turn is close to HOH721; HOH598 WHICH IS CLOSE TO HOH831; HOH70 WHICH IS CLOSE TO HOH364; HOH401 WHICH IS CLOSE TO HOH846; HOH462 WHICH IS CLOSE TO HOH465; HOH451 WHICH IS CLOSE TO HOH719; HOH423 WHICH IS CLOSE TO HOH429; HOH358 WHICH IS CLOSE TO HOH910; HOH30 WHICH IS CLOSE TO A SYMMETRY-RELATED EQUIVALENT OF ITSELF; HOH25 WHICH IS CLOSE TO A SYMMETRY-RELATED EQUIVALENT OF HOH318; HOH38 WHICH IS CLOSE TO A SYMMETRY-RELATED EQUIVALENT OF HOH694; HOH146 WHICH IS CLOSE TO A SYMMETRY-RELATED EQUIVALENT OF HOH375; HOH17 WHICH IS CLOSE TO A SYMMETRY-RELATED EQUIVALENT OF HOH82.
RfactorNum. reflection% reflection
Rfree0.246 1963 10 %
Rwork0.2 --
obs0.2 19808 67.9 %
Refinement stepCycle: LAST / Resolution: 1.65→7.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4149 0 86 1047 5282
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.018
X-RAY DIFFRACTIONx_angle_deg4.1
X-RAY DIFFRACTIONx_dihedral_angle_d24.6
X-RAY DIFFRACTIONx_improper_angle_d0.43
LS refinement shellResolution: 1.65→1.72 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.449 140 10 %
Rwork0.41 1014 -
obs--32.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1upa7538_parmallh3x.proupa7538_topallh6x.pro
X-RAY DIFFRACTION2upa7538_param11_ucsf.wat
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Lowest resolution: 7.5 Å / σ(F): 1.9 / % reflection Rfree: 10 % / Rfactor obs: 0.203 / Rfactor Rwork: 0.2
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_deg4.1
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg24.6
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.43
LS refinement shell
*PLUS
Rfactor Rfree: 0.449 / % reflection Rfree: 10 % / Rfactor Rwork: 0.41

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