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- PDB-4jk6: Human urokinase-type Plasminogen Activator (uPA) in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4jk6
TitleHuman urokinase-type Plasminogen Activator (uPA) in complex with a bicyclic peptide inhibitor (UK18-D-Aba)
Components
  • Urokinase-type plasminogen activatorUrokinase
  • bicyclic peptide UK18-D-Aba inhibitor of uPA
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease / chymotrypsin fold / urokinase-type plasminogen activator / bicyclic peptide inhibitor / D-amino acids / 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 / negative regulation of plasminogen activation / regulation of smooth muscle cell migration / regulation of signaling receptor activity ...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
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. ...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
bicyclic peptide UK18-D-Aba inhibitor of uPA / 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: 2.2 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 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_initial_refinement_model / struct_conn / 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 / _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 1.4Dec 6, 2023Group: Data collection / Derived calculations / Category: chem_comp_atom / chem_comp_bond / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag

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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-Aba inhibitor of uPA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,4649
Polymers29,4052
Non-polymers1,0597
Water1,982110
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-64 kcal/mol
Surface area11990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.219, 121.219, 42.731
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 / Urokinase / 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: C299A, N322Q
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-Aba inhibitor of uPA


Type: Cyclic peptide / Class: Inhibitor / Mass: 1819.058 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Synthetic construct (others) / References: bicyclic peptide UK18-D-Aba inhibitor of uPA

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Non-polymers , 5 types, 117 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400 / Polyethylene glycol


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-Aba inhibitor of uPA
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 110 / 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: 40.14 %
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: 2.2→33.16 Å / Num. all: 11881 / Num. obs: 11879 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 4.8 % / Biso Wilson estimate: 30 Å2 / Rmerge(I) obs: 0.094 / Rsym value: 0.048 / Net I/σ(I): 10.7
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.438 / Mean I/σ(I) obs: 3.7 / Num. unique all: 1037 / Rsym value: 0.308 / % possible all: 100

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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: 2.2→33.16 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.945 / SU B: 11.095 / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.333 / ESU R Free: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20526 564 4.7 %RANDOM
Rwork0.15343 ---
all0.15586 11881 --
obs0.15586 11311 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: 40.333 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0.47 Å20 Å2
2---0.47 Å2-0 Å2
3---1.54 Å2
Refinement stepCycle: LAST / Resolution: 2.2→33.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2058 0 49 110 2217
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192176
X-RAY DIFFRACTIONr_bond_other_d0.0010.022004
X-RAY DIFFRACTIONr_angle_refined_deg1.8451.9682949
X-RAY DIFFRACTIONr_angle_other_deg0.8513.0064611
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3735264
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.34522.97994
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.46115.014358
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.2721516
X-RAY DIFFRACTIONr_chiral_restr0.0960.2313
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212426
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02505
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 43 -
Rwork0.255 853 -
obs-896 100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.9957-0.9588-0.14463.836-0.06761.4802-0.0872-0.0374-0.0862-0.0220.09480.37830.1443-0.2303-0.00770.15260.0275-0.01280.1516-0.02140.0895-35.498113.308-2.482
224.11-16.8935-5.573520.91846.28127.0205-0.2953-0.357-0.48260.67360.27840.18940.4967-0.13480.0170.20450.00670.03250.18480.06750.0868-35.584106.1315.604
36.338-1.21870.675.0728-0.52331.841-0.0629-0.49090.50770.38480.25750.3985-0.1425-0.4536-0.19450.12180.07760.02040.1847-0.03160.1752-37.155121.0622.773
44.0544-5.5454-2.045617.3163-10.274424.2366-0.6777-0.30270.35891.38270.4310.4279-1.4087-0.48550.24670.48210.0799-0.22080.1664-0.31080.7563-24.897135.7585.176
52.88410.174-0.62983.3965-0.04881.59320.09620.19340.4202-0.3371-0.1934-0.2379-0.10640.14130.09720.20090.07680.0220.13020.02450.1341-25.076116.919-10.761
61.65023.0388-0.315112.4373-1.91434.3071-0.03530.32040.9678-0.12870.36020.5283-0.8123-0.1763-0.32490.17870.0170.0750.15310.23250.838-20.331132.5-12.809
74.34360.6604-0.12343.25-0.21651.28310.06080.02690.9838-0.18550.0542-0.3951-0.3270.1108-0.11490.17840.01230.05950.10960.01560.3581-24.124127.494-9.485
83.3194-0.4183-0.52842.38440.05921.95110.12320.08260.9659-0.19950.105-0.2677-0.26570.0318-0.22820.19710.0450.01170.1320.02940.4673-28.204128.988-7.358
91.87042.8037-1.788839.910615.871211.4920.4993-0.5836-0.06192.3632-0.5567-0.55620.23390.43570.05750.44390.1295-0.15040.7695-0.45960.4958-37.779130.0279.823
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-IDSelection
1X-RAY DIFFRACTION1A16 - 77
2X-RAY DIFFRACTION2A78 - 84
3X-RAY DIFFRACTION3A85 - 123
4X-RAY DIFFRACTION4A124 - 128
5X-RAY DIFFRACTION5A129 - 156
6X-RAY DIFFRACTION6A157 - 170157 to 170B
7X-RAY DIFFRACTION7A171 - 206
8X-RAY DIFFRACTION8A207 - 237
9X-RAY DIFFRACTION9A238 - 242

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