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- PDB-3ig6: Low molecular weigth human Urokinase type Plasminogen activator 2... -

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Basic information

Entry
Database: PDB / ID: 3ig6
TitleLow molecular weigth human Urokinase type Plasminogen activator 2-[6-(3'-Aminomethyl-biphenyl-3-yloxy)-4-(3-dimethylamino-pyrrolidin-1-yl)-3,5-difluoro-pyridin-2-yloxy]-4-dimethylamino-benzoic acid complex
Components(Urokinase-type plasminogen activator) x 2
KeywordsHYDROLASE / SELECTIVE / S1 SITE INHIBITOR / STRUCTURE-BASED DRUG DESIGN / UROKINASE / Blood coagulation / Disulfide bond / EGF-like domain / Fibrinolysis / Glycoprotein / Kringle / Pharmaceutical / Phosphoprotein / Plasminogen activation / Polymorphism / Protease / Secreted / Serine protease / Zymogen
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
Chem-438 / PHOSPHATE ION / Urokinase-type plasminogen activator / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsAdler, M. / Whitlow, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)
Authors: West, C.W. / Adler, M. / Arnaiz, D. / Chen, D. / Chu, K. / Gualtieri, G. / Ho, E. / Huwe, C. / Light, D. / Phillips, G. / Pulk, R. / Sukovich, D. / Whitlow, M. / Yuan, S. / Bryant, J.
History
DepositionJul 27, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 13, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 16, 2011Group: Atomic model
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Urokinase-type plasminogen activator
B: Urokinase-type plasminogen activator
C: Urokinase-type plasminogen activator
D: Urokinase-type plasminogen activator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,6397
Polymers62,3374
Non-polymers1,3023
Water4,089227
1
A: Urokinase-type plasminogen activator
B: Urokinase-type plasminogen activator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,7723
Polymers31,1692
Non-polymers6041
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Urokinase-type plasminogen activator
D: Urokinase-type plasminogen activator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8674
Polymers31,1692
Non-polymers6992
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Urokinase-type plasminogen activator
B: Urokinase-type plasminogen activator
C: Urokinase-type plasminogen activator
D: Urokinase-type plasminogen activator
hetero molecules

A: Urokinase-type plasminogen activator
B: Urokinase-type plasminogen activator
C: Urokinase-type plasminogen activator
D: Urokinase-type plasminogen activator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,27914
Polymers124,6748
Non-polymers2,6056
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area11480 Å2
ΔGint-55 kcal/mol
Surface area37020 Å2
MethodPISA
4


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4080 Å2
ΔGint-22 kcal/mol
Surface area20170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.855, 52.294, 72.580
Angle α, β, γ (deg.)90.00, 90.23, 90.00
Int Tables number3
Space group name H-MP121
Components on special symmetry positions
IDModelComponents
11B-839-

HOH

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Components

#1: Protein/peptide Urokinase-type plasminogen activator / U-plasminogen activator / uPA / Urokinase-type plasminogen activator long chain A / Urokinase-type ...U-plasminogen activator / uPA / Urokinase-type plasminogen activator long chain A / Urokinase-type plasminogen activator short chain A / Urokinase-type plasminogen activator chain B


Mass: 2708.183 Da / Num. of mol.: 2 / Fragment: FRAGMENT OF LIGHT CHAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLAU / Production host: Escherichia coli (E. coli)
References: UniProt: Q5SWW9, UniProt: P00749*PLUS, u-plasminogen activator
#2: Protein Urokinase-type plasminogen activator / U-plasminogen activator / uPA / Urokinase-type plasminogen activator long chain A / Urokinase-type ...U-plasminogen activator / uPA / Urokinase-type plasminogen activator long chain A / Urokinase-type plasminogen activator short chain A / Urokinase-type plasminogen activator chain B


Mass: 28460.412 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLAU / Production host: Escherichia coli (E. coli)
References: UniProt: Q5SWW9, UniProt: P00749*PLUS, u-plasminogen activator
#3: Chemical ChemComp-438 / 2-[(6-{[3'-(aminomethyl)biphenyl-3-yl]oxy}-4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3,5-difluoropyridin-2-yl)oxy]-4-(dimethylamino)benzoic acid


Mass: 603.659 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H35F2N5O4
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsAUTHORS STATE THAT THE ACTIVE FORM OF UROKINASE IS CREATED BY A PROTEOLYTIC CLIP, THUS IT HAS TWO CHAINS

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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: 2.16 Å3/Da / Density % sol: 42.98 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 20.4 g/l, 1 mM ligand in 50 mM Tris pH 7.4, 5 mM NaCl, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 22, 2003
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→20 Å / Num. all: 48073 / Num. obs: 47497 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.45 % / Biso Wilson estimate: 12.4 Å2 / Rsym value: 0.0535 / Net I/σ(I): 15.15
Reflection shellResolution: 1.83→1.94 Å / Redundancy: 2.26 % / Mean I/σ(I) obs: 2.6 / Num. unique all: 5887 / Rsym value: 0.244 / % possible all: 99.4

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Processing

Software
NameClassification
BOSdata collection
CNXrefinement
XTALVIEWrefinement
X-GENdata reduction
X-GENdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1LMW

1lmw


Resolution: 1.83→19.83 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 132827.96 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.228 1684 3.9 %RANDOM
Rwork0.197 ---
obs0.198 42641 90.4 %-
all-46597 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.936 Å2 / ksol: 0.403955 e/Å3
Displacement parametersBiso mean: 22.9 Å2
Baniso -1Baniso -2Baniso -3
1-1.5 Å20 Å24.94 Å2
2--1.59 Å20 Å2
3----3.1 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.12 Å
Refinement stepCycle: LAST / Resolution: 1.83→19.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3939 0 93 227 4259
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_mcbond_it1.431.5
X-RAY DIFFRACTIONc_mcangle_it2.172
X-RAY DIFFRACTIONc_scbond_it2.622
X-RAY DIFFRACTIONc_scangle_it4.063
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.83→1.94 Å / Rfactor Rfree error: 0.019 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.29 232 3.8 %
Rwork0.234 5887 -
obs-5887 78.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.pprotein.top
X-RAY DIFFRACTION2water_rep.parwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4438.par438.top
X-RAY DIFFRACTION5&_1_PARAMETER_INFILE_5&_1_TOPOLOGY_INFILE_5

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