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PDBsum entry 3laq

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase receptor PDB id
3laq
Jmol
Contents
Protein chains
124 a.a. *
258 a.a. *
Ligands
NAG-NAG ×2
NAG ×6
* Residue conservation analysis
PDB id:
3laq
Name: Hydrolase/hydrolase receptor
Title: Structure-based engineering of species selectivity in the up interaction
Structure: Urokinase-type plasminogen activator. Chain: a, b. Fragment: unp residues 21-154. Synonym: u-plasminogen activator, upa, urokinase-type plasm activator long chain a, urokinase-type plasminogen activato chain a, urokinase-type plasminogen activator chain b. Engineered: yes. Urokinase plasminogen activator surface receptor. Chain: u, v.
Source: Mus musculus. Mouse. Organism_taxid: 10090. Gene: plau. Expressed in: drosophila. Expression_system_taxid: 7215. Gene: plaur.
Resolution:
3.20Å     R-factor:   0.237     R-free:   0.341
Authors: M.Huang
Key ref: L.Lin et al. (2010). Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy. J Biol Chem, 285, 10982-10992. PubMed id: 20133942
Date:
06-Jan-10     Release date:   02-Feb-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P06869  (UROK_MOUSE) -  Urokinase-type plasminogen activator
Seq:
Struc:
433 a.a.
124 a.a.
Protein chains
Pfam   ArchSchema ?
P35456  (UPAR_MOUSE) -  Urokinase plasminogen activator surface receptor
Seq:
Struc:
327 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.3.4.21.73  - U-plasminogen activator.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   7 terms 
  Biochemical function     protein binding     4 terms  

 

 
J Biol Chem 285:10982-10992 (2010)
PubMed id: 20133942  
 
 
Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy.
L.Lin, H.Gårdsvoll, Q.Huai, M.Huang, M.Ploug.
 
  ABSTRACT  
 
The high affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) is decisive for cell surface-associated plasminogen activation. Because plasmin activity controls fibrinolysis in a variety of pathological conditions, including cancer and wound healing, several intervention studies have focused on targeting the uPA.uPAR interaction in vivo. Evaluations of such studies in xenotransplanted tumor models are, however, complicated by the pronounced species selectivity in this interaction. We now report the molecular basis underlying this difference by solving the crystal structure for the murine uPA.uPAR complex and demonstrate by extensive surface plasmon resonance studies that the kinetic rate constants for this interaction can be swapped completely between these orthologs by exchanging only two residues. This study not only discloses the structural basis required for a successful rational design of the species selectivity in the uPA.uPAR interaction, which is highly relevant for functional studies in mouse models, but it also suggests the possible development of general inhibitors that will target the uPA.uPAR interaction across species barriers.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21454081 M.De Souza, H.Matthews, J.A.Lee, M.Ranson, and M.J.Kelso (2011).
Small molecule antagonists of the urokinase (uPA): urokinase receptor (uPAR) interaction with high reported potencies show only weak effects in cell-based competition assays employing the native uPAR ligand.
  Bioorg Med Chem, 19, 2549-2556.  
20466854 B.M.Connolly, E.Y.Choi, H.Gårdsvoll, A.L.Bey, B.M.Currie, T.Chavakis, S.Liu, A.Molinolo, M.Ploug, S.H.Leppla, and T.H.Bugge (2010).
Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation.
  Blood, 116, 1593-1603.  
20799877 S.Praharaj, D.Overbey, and M.F.Giblin (2010).
Radiometallated peptides targeting guanylate cyclase C and the urokinase-type plasminogen activator receptor.
  Future Oncol, 6, 1325-1337.  
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