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- PDB-1o5c: Dissecting and Designing Inhibitor Selectivity Determinants at th... -

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Basic information

Entry
Database: PDB / ID: 1o5c
TitleDissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
Components(Urokinase-type plasminogen activator) x 2
KeywordsBLOOD CLOTTING / hydrolase / Ala190 uPA / S1 site / selectivity / conserved water displacement hydrogen bond deficit / trypsin / thrombin / hepsin / factor VIIa
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
CITRIC ACID / Chem-CR9 / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.63 Å
AuthorsKatz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. ...Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
CitationJournal: J.Mol.Biol. / Year: 2004
Title: Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA)
Authors: Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
History
DepositionSep 9, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Category: 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 1.4Dec 27, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)31,8945
Polymers31,1282
Non-polymers7673
Water3,693205
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-3 kcal/mol
Surface area11940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.71, 50.28, 66.20
Angle α, β, γ (deg.)90.0, 113.04, 90.0
Int Tables number5
Cell settingmonoclinic
Space group name H-MC121

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Components

#1: Protein/peptide Urokinase-type plasminogen activator / uPA / U-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) / Gene: PLAU / Plasmid: PPIC9LMWUPA-ALA190 / Production host: Pichia pastoris (fungus) / References: UniProt: P00749, u-plasminogen activator
#2: Protein Urokinase-type plasminogen activator / E.C.3.4.21.73 / uPA / U-plasminogen activator


Mass: 28419.428 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN / Mutation: N145A/S190A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLAU / Plasmid: PPIC9LMWUPA-ALA190 / Production host: Pichia pastoris (fungus) / References: UniProt: P00749, u-plasminogen activator
#3: Chemical ChemComp-CR9 / 2-{5-[AMINO(IMINIO)METHYL]-6-FLUORO-1H-BENZIMIDAZOL-2-YL}-6-[(2-METHYLCYCLOHEXYL)OXY]BENZENOLATE / CRA_11092


Mass: 382.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23FN4O2
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O

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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: 38.81 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5
Details: 2-propanol, PEG 4000, pH 6.5, vapor diffusion at 298 K, pH 6.5, pH 6.50

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Data collection

DiffractionMean temperature: 285 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 1, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.63→41.8 Å / Num. all: 31031 / Num. obs: 30503 / % possible obs: 98.3 % / Observed criterion σ(I): 0 / Redundancy: 2.4 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 8
Reflection shellResolution: 1.63→1.7 Å / % possible obs: 38.36 % / Rmerge(I) obs: 0.4 / Num. unique all: 3811

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Processing

Software
NameVersionClassification
CrystalClear1.3data collection
CrystalClear1.3data reduction
X-PLOR3.851refinement
CrystalClear(MSC/RIGAKU)data scaling
Quantamodel building
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.63→7 Å / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: X-PLOR force field
Details: Only Leu_A9 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 Leu_A9 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: Ile_B16, Met_B47, Glu_B84, Glu_B86, Thr_B139, Gln_B192, Leu_B209, Val_B213, Pro_B225, Leu_B235. No energy terms are included among HOH_383, and OgSer195, and O6' of the inhibitor. These atoms form a very short multi-centered hydrogen-bonding network. HOH_597 makes short hydrogen bonds with the amidine nitrogens of the inhibitor. Disordered waters are: AHOH_603 which is close to BHOH_603; No energy terms between citrate 1 and 2 are included because they are hydrogen-bonded to one another via short hydrogen bonds between carboxylate / hydroxyl groups.
RfactorNum. reflection% reflection
Rfree0.219 2410 10 %
Rwork0.191 --
obs0.193 24059 78.63 %
all-30598 -
Refinement stepCycle: LAST / Resolution: 1.63→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4085 0 87 618 4790
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.017
X-RAY DIFFRACTIONx_angle_deg4

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