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- PDB-3qn7: Potent and selective bicyclic peptide inhibitor (UK18) of human u... -

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Basic information

Entry
Database: PDB / ID: 3qn7
TitlePotent and selective bicyclic peptide inhibitor (UK18) of human urokinase-type plasminogen activator(uPA)
Components
  • Bicyclic peptide inhibitor
  • Urokinase-type plasminogen activatorUrokinase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Bicyclic peptide inhibitor / Chymotrypsin fold / Serine protease / Urokinase receptor (uPAR) / Extracellular / 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 / tertiary granule membrane / regulation of cell adhesion mediated by integrin / negative regulation of fibrinolysis / specific granule membrane / regulation of cell adhesion / 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
1,3,5-tris(bromomethyl)benzene / Urokinase-type plasminogen activator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsAngelini, A. / Cendron, L. / Touati, J. / Winter, G. / Zanotti, G. / Heinis, C.
Citation
Journal: Acs Chem.Biol. / Year: 2012
Title: Bicyclic peptide inhibitor reveals large contact interface with a protease target
Authors: Angelini, A. / Cendron, L. / Chen, S. / Touati, J. / Winter, G. / Zanotti, G. / Heinis, C.
#1: Journal: 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.
#2: Journal: Structure / Year: 1995
Title: The crystal structure of the catalytic domain of human urokinase-type plasminogen activator
Authors: Spraggon, G. / Phillips, C. / Nowak, U.K. / Ponting, C.P. / Saunders, D. / Dobson, C.M. / Stuart, D.I. / Jones, E.Y.
History
DepositionFeb 8, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 15, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2013Group: Database references
Revision 1.2Nov 1, 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_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 / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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 inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,5923
Polymers30,2352
Non-polymers3571
Water2,378132
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-6 kcal/mol
Surface area11400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.250, 121.250, 42.720
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 Urokinase-type plasminogen activator / Urokinase / U-plasminogen activator / uPA


Mass: 28442.373 Da / Num. of mol.: 1
Fragment: Catalytic domain, Urokinase-type plasminogen activator chain B
Mutation: C122A, N145Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLAU / Plasmid: pSecTagA / Cell (production host): mammalian cells
Cell line (production host): Human embryonic kidney cells (HEK-293)
Production host: Homo sapiens (human) / References: UniProt: P00749, u-plasminogen activator
#2: Protein/peptide Bicyclic peptide inhibitor / UK18


Mass: 1792.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Chemical synthesis
#3: Chemical ChemComp-ZBR / 1,3,5-tris(bromomethyl)benzene


Mass: 356.880 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H9Br3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 132 / 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 Å3/Da / Density % sol: 38.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.3
Details: 2M ammonium sulfate, 0.05M sodium citrate, 5%(v/v) PEG 400, pH 4.3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.939 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 29, 2010 / Details: Toroidal focusing mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.939 Å / Relative weight: 1
ReflectionResolution: 1.9→39.57 Å / Num. all: 18155 / Num. obs: 18155 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.4 % / Rmerge(I) obs: 0.079 / Net I/σ(I): 12.2
Reflection shellResolution: 1.9→2 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.405 / Mean I/σ(I) obs: 3.9 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASESphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NWN.pdb

2nwn


Resolution: 1.9→39.57 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.922 / SU B: 4.495 / SU ML: 0.134 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25233 946 5.1 %RANDOM
Rwork0.19527 ---
all0.19822 18155 --
obs0.19822 17487 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 34.287 Å2
Baniso -1Baniso -2Baniso -3
1--0.96 Å2-0.48 Å20 Å2
2---0.96 Å20 Å2
3---1.44 Å2
Refinement stepCycle: LAST / Resolution: 1.9→39.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2050 0 9 132 2191
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0212113
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.91.9482862
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4625259
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.91122.90393
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.77215354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5941516
X-RAY DIFFRACTIONr_chiral_restr0.1540.2305
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211602
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3291.51292
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.34422085
X-RAY DIFFRACTIONr_scbond_it3.223821
X-RAY DIFFRACTIONr_scangle_it4.944.5777
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 79 -
Rwork0.283 1313 -
obs--100 %

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