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- PDB-2nwn: New Pharmacophore for Serine Protease Inhibition Revealed by Crys... -

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Basic information

Entry
Database: PDB / ID: 2nwn
TitleNew Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1
Components
  • Plasminogen activator, urokinase
  • upain-1
KeywordsHYDROLASE / urokinase-type plasminogen activator / peptidyl inhibitor / pharmacophore / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


neutrophil degranulation / 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 ...neutrophil degranulation / 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 / 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
Urokinase-type plasminogen activator / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / EGF-like domain profile. ...Urokinase-type plasminogen activator / 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
Urokinase-type plasminogen activator / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsZhao, G. / Yuan, C. / Wind, T. / Andreasen, P.A. / Huang, Z. / Huang, M. / Structural Genomics Consortium (SGC)
CitationJournal: J.Struct.Biol. / Year: 2007
Title: Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1
Authors: Zhao, G. / Yuan, C. / Wind, T. / Huang, Z. / Andreasen, P.A. / Huang, M.
History
DepositionNov 16, 2006Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 16, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Plasminogen activator, urokinase
B: upain-1


Theoretical massNumber of molelcules
Total (without water)29,9372
Polymers29,9372
Non-polymers00
Water2,396133
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.481, 120.481, 42.117
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Plasminogen activator, urokinase / / uPA


Mass: 28442.373 Da / Num. of mol.: 1 / Fragment: C-terminal domain, residues 16-250 / Mutation: C122A/N145Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pPICZALPHAA / Production host: Pichia pastoris (fungus) / Strain (production host): X-33 / References: UniProt: Q53XS3, UniProt: P00749*PLUS
#2: Protein/peptide upain-1


Mass: 1494.745 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: This peptide was chemically synthesized by solid phase synthesis and purified by reverse phase HPLC.
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.1 Å3/Da / Density % sol: 37.38 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 0.05M sodium citrate, 1.95M (NH4)2SO4, 0.05% NaN3, 5% PEG 400, pH 4.50, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorType: BRUKER SMART 6000 / Detector: CCD / Date: Mar 25, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.15→60.24 Å / Num. obs: 16947 / % possible obs: 99.64 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 6.89 % / Biso Wilson estimate: 11.1 Å2 / Rmerge(I) obs: 0.1233 / Rsym value: 0.1261 / Net I/σ(I): 5.83
Reflection shellResolution: 2.15→2.28 Å / Redundancy: 6.89 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 1.94 / % possible all: 99.8

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Processing

Software
NameVersionClassification
CNS1.1refinement
PROTEUM PLUSPLUSdata collection
PROTEUM PLUSPLUSdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1F5K

1f5k


Resolution: 2.15→60.24 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 2268857.23 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.261 1027 8.3 %RANDOM
Rwork0.218 ---
obs0.218 12396 100 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.9508 Å2 / ksol: 0.380482 e/Å3
Displacement parametersBiso mean: 24.4 Å2
Baniso -1Baniso -2Baniso -3
1--5.25 Å2-0.92 Å20 Å2
2---5.25 Å20 Å2
3---10.5 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.15→60.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2000 0 0 133 2133
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.014
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg2.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d25.6
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d2.04
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.461.5
X-RAY DIFFRACTIONc_mcangle_it2.342
X-RAY DIFFRACTIONc_scbond_it1.982
X-RAY DIFFRACTIONc_scangle_it2.832.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 2.15→2.28 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rwork0.268 2059 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2TEMP.DUMMY
X-RAY DIFFRACTION3CARBOHYDRATE.PARAM
X-RAY DIFFRACTION4WATER_REP.PARAM
X-RAY DIFFRACTION5ION.PARAM

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