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- PDB-4jk5: Human urokinase-type Plasminogen Activator (uPA) in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4jk5
TitleHuman urokinase-type Plasminogen Activator (uPA) in complex with a bicyclic peptide inhibitor (UK18-D-Ser)
Components
  • Urokinase-type plasminogen activator
  • bicyclic peptide UK18-D-Ser, uPA inhibitor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease / chymotrypsin fold / urokinase-type plasminogen activator / bicyclic peptide inhibitor / D-amino acid / HYDROLASE-HYDROLASE INHIBITOR complex
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
bicyclic peptide UK18-D-Ser / 1,3,5-tris(bromomethyl)benzene / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
Synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsButh, S.A. / Leiman, P.G. / Chen, S. / Heinis, C.
CitationJournal: Chembiochem / Year: 2013
Title: Improving binding affinity and stability of Peptide ligands by substituting glycines with d-amino acids.
Authors: Chen, S. / Gfeller, D. / Buth, S.A. / Michielin, O. / Leiman, P.G. / Heinis, C.
History
DepositionMar 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Jun 2, 2021Group: Database references / Derived calculations / Source and taxonomy
Category: entity_src_gen / struct_conn ...entity_src_gen / struct_conn / struct_ref_seq_dif / struct_site
Item: _entity_src_gen.host_org_common_name / _entity_src_gen.pdbx_host_org_cell_line ..._entity_src_gen.host_org_common_name / _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_value_order / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Sep 20, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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: bicyclic peptide UK18-D-Ser, uPA inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,50210
Polymers29,4072
Non-polymers1,0948
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-78 kcal/mol
Surface area11760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.239, 121.239, 42.631
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: 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: 27586.420 Da / Num. of mol.: 1 / Fragment: Catalytic domain / Mutation: C122A, N145Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: 9606 / Gene: PLAU / Plasmid: pSecTagA / Cell line (production host): HEK-293 / Production host: Homo sapiens (human) / References: UniProt: P00749, u-plasminogen activator
#2: Protein/peptide bicyclic peptide UK18-D-Ser, uPA inhibitor


Type: Cyclic peptide / Class: Inhibitor / Mass: 1821.031 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Synthetic construct (others) / References: bicyclic peptide UK18-D-Ser

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Non-polymers , 5 types, 112 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#6: Chemical ChemComp-ZBR / 1,3,5-tris(bromomethyl)benzene


Type: Cyclic peptide / Class: Inhibitor / Mass: 356.880 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H9Br3 / References: bicyclic peptide UK18-D-Ser
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / 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: 2.05 Å3/Da / Density % sol: 40.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.9
Details: 50mM Na3(cit) pH 4.9, 5% v/v PEG400, 1.8M (NH4)2SO4, 0.05% NaN3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 1, 2012 / Details: mirrors
RadiationMonochromator: Bartels Monochromator with dual channel cut crystals (DCCM) in (+--+) geometry and a toroidal mirror (M2)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.55→33.09 Å / Num. all: 33910 / Num. obs: 33907 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 4.7 % / Biso Wilson estimate: 18.94 Å2 / Rmerge(I) obs: 0.037 / Rsym value: 0.019 / Net I/σ(I): 17.6
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.416 / Mean I/σ(I) obs: 3.5 / Num. unique all: 7729 / Rsym value: 0.217 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2NWN

2nwn


Resolution: 1.55→33.09 Å / Cor.coef. Fo:Fc: 0.98 / Cor.coef. Fo:Fc free: 0.961 / SU B: 5.008 / SU ML: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.098 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21283 1719 5.1 %RANDOM
Rwork0.14236 ---
all0.14609 33910 --
obs0.14609 32177 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.459 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0.1 Å20 Å2
2---0.1 Å2-0 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.55→33.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2058 0 50 104 2212
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192206
X-RAY DIFFRACTIONr_bond_other_d0.0010.022035
X-RAY DIFFRACTIONr_angle_refined_deg1.9831.9672992
X-RAY DIFFRACTIONr_angle_other_deg0.9293.0064683
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7385270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.87522.70896
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.14615366
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5281518
X-RAY DIFFRACTIONr_chiral_restr0.120.2316
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212471
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02518
X-RAY DIFFRACTIONr_rigid_bond_restr5.96134241
X-RAY DIFFRACTIONr_sphericity_free32.22534
X-RAY DIFFRACTIONr_sphericity_bonded27.60754256
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 131 -
Rwork0.192 2363 -
obs-2494 99.2 %

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