1VJA

Urokinase Plasminogen Activator B-Chain-JT463 Complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.232 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents

Schweinitz, A.Steinmetzer, T.Banke, I.J.Arlt, M.J.E.Stuerzebecher, A.Schuster, O.Geissler, A.Giersiefen, H.Zeslawska, E.Jacob, U.Kruger, A.Stuerzebecher, J.

(2004) J Biol Chem 279: 33613-33622

  • DOI: https://doi.org/10.1074/jbc.M314151200
  • Primary Citation of Related Structures:  
    1SC8, 1VJ9, 1VJA

  • PubMed Abstract: 

    The serine protease urokinase-type plasminogen activator (uPA) interacts with a specific receptor (uPAR) on the surface of various cell types, including tumor cells, and plays a crucial role in pericellular proteolysis. High levels of uPA and uPAR often correlate with poor prognosis of cancer patients. Therefore, the specific inhibition of uPA with small molecule active-site inhibitors is one strategy to decrease the invasive and metastatic activity of tumor cells. We have developed a series of highly potent and selective uPA inhibitors with a C-terminal 4-amidinobenzylamide residue. Optimization was directed toward reducing the fast elimination from circulation that was observed with initial analogues. The x-ray structures of three inhibitor/uPA complexes have been solved and were used to improve the inhibition efficacy. One of the most potent and selective derivatives, benzylsulfonyl-D-Ser-Ser-4-amidinobenzylamide (inhibitor 26), inhibits uPA with a Ki of 20 nm. This inhibitor was used in a fibrosarcoma model in nude mice using lacZ-tagged human HT1080 cells, to prevent experimental lung metastasis formation. Compared with control (100%), an inhibitor dose of 2 x 1.5 mg/kg/day reduced the number of experimental metastases to 4.6 +/- 1%. Under these conditions inhibitor 26 also significantly prolonged survival. All mice from the control group died within 43 days after tumor cell inoculation, whereas 50% of mice from the inhibitor-treated group survived more than 117 days. This study demonstrates that the specific inhibition of uPA by these inhibitors may be a useful strategy for the treatment of cancer to prevent metastasis.


  • Organizational Affiliation

    Curacyte Chemistry GmbH, Winzerlaer Strasse 2, D-07745 Jena, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
plasminogen activator, urokinaseA [auth U]262Homo sapiensMutation(s): 1 
Gene Names: Homo
EC: 3.4.21.73
UniProt & NIH Common Fund Data Resources
Find proteins for P00749 (Homo sapiens)
Explore P00749 
Go to UniProtKB:  P00749
PHAROS:  P00749
GTEx:  ENSG00000122861 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00749
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7IN
Query on 7IN

Download Ideal Coordinates CCD File 
D [auth U]N-(BENZYLSULFONYL)SERYL-N~1~-{4-[(Z)-AMINO(IMINO)METHYL]BENZYL}SERINAMIDE
C21 H27 N5 O6 S
ZNOKJHWJKULOGM-ZWKOTPCHSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth U],
C [auth U]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
7IN Binding MOAD:  1VJA Ki: 20 (nM) from 1 assay(s)
PDBBind:  1VJA Ki: 20 (nM) from 1 assay(s)
BindingDB:  1VJA Ki: 20 (nM) from 1 assay(s)
IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.232 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.065α = 90
b = 55.004β = 90
c = 81.924γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
CNSrefinement
CCP4data scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-06-22
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-23
    Changes: Data collection, Refinement description