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PDBsum entry 2fd6
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protein ligands Protein-protein interface(s) links
Immune system, hydrolase PDB id
2fd6

 

 

 

 

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Contents
Protein chains
122 a.a. *
214 a.a. *
212 a.a. *
249 a.a. *
Ligands
NAG-FUC
NAG-NAG
SO4
ETX ×3
EDO ×2
PGE
NDG
PG4
Waters ×336
* Residue conservation analysis
PDB id:
2fd6
Name: Immune system, hydrolase
Title: Structure of human urokinase plasminogen activator in complex with urokinase receptor and an anti-upar antibody at 1.9 a
Structure: Urokinase-type plasminogen activator. Chain: a. Fragment: amino terminal residues 31-152. Engineered: yes. L chain of fab of atn-615 anti-upar antibody. Chain: l. H chain of fab of atn-615 anti-upar antibody. Chain: h. Urokinase plasminogen activator surface receptor.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: drosophila. Expression_system_taxid: 7215. Expression_system_cell_line: s2 cells. Mus musculus. House mouse. Organism_taxid: 10090.
Biol. unit: Tetramer (from PQS)
Resolution:
1.90Å     R-factor:   0.239     R-free:   0.276
Authors: M.Huang,Q.Huai,Y.Li
Key ref:
Q.Huai et al. (2006). Structure of human urokinase plasminogen activator in complex with its receptor. Science, 311, 656-659. PubMed id: 16456079 DOI: 10.1126/science.1121143
Date:
13-Dec-05     Release date:   21-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00749  (UROK_HUMAN) -  Urokinase-type plasminogen activator from Homo sapiens
Seq:
Struc: 		431 a.a.
122 a.a.*
Protein chain
Pfam   ArchSchema ?
Q52L64  (Q52L64_MOUSE) -  ENSMUSG00000076577 protein from Mus musculus
Seq:
Struc: 		240 a.a.
214 a.a.*
Protein chain
Pfam   ArchSchema ?
Q924Q0  (Q924Q0_MOUSE) -  V165-D-J-C mu protein (Fragment) from Mus musculus
Seq:
Struc: 		143 a.a.
212 a.a.*
Protein chain
Pfam   ArchSchema ?
Q03405  (UPAR_HUMAN) -  Urokinase plasminogen activator surface receptor from Homo sapiens
Seq:
Struc: 		335 a.a.
249 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 95 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: 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.

 

 
DOI no: 10.1126/science.1121143 Science 311:656-659 (2006)
PubMed id: 16456079  
 
 
Structure of human urokinase plasminogen activator in complex with its receptor.
Q.Huai, A.P.Mazar, A.Kuo, G.C.Parry, D.E.Shaw, J.Callahan, Y.Li, C.Yuan, C.Bian, L.Chen, B.Furie, B.C.Furie, D.B.Cines, M.Huang.
 
  ABSTRACT  
 
The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation. We report the crystal structure at 1.9 angstroms of the urokinase receptor complexed with the urokinase amino-terminal fragment and an antibody against the receptor. The three domains of urokinase receptor form a concave shape with a central cone-shaped cavity where the urokinase fragment inserts. The structure provides insight into the flexibility of the urokinase receptor that enables its interaction with a wide variety of ligands and a basis for the design of urokinase-urokinase receptor antagonists.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. X-ray structure of the suPAR-ATF-ATN615 complex. (A) Stereo view of the structure of the suPAR-ATF-ATN615 complex. In the ribbon diagram of the ternary complex, the D1 domain of suPAR is shown in orange, the D2 domain in magenta, and the D3 domain in green. The ATF is shown in cyan, light chain of the antibody ATN615 in light blue, and the heavy chain in dark blue. Carbohydrates in suPAR are shown as red sticks. Disulfide bonds are shown in dashed lines colored as is the backbone to which they are attached. (B) Ribbon structure of ATF. The GFD domain is shown in cyan and the kringle domain in dark salmon. The residues Leu14, His41, Ile^44, Asp45, Arg59, Leu92, and Tyr101 involved in domain interactions are shown as sticks. -loop (residues 23 to 29) connects two ß strands (residues 18 to 22 and 30 to 32) in the GFD domain. The kringle domain contains two strands (residues 112 to 117 and 120 to 125) and two short helices (78 to 81 and 91 to 94). All figures were made by PyMOL (23). 		Figure 3.
Fig. 3. The suPAR-ATF binding surface. The carbon atoms of the D1 domain of uPAR are shown in orange, the D2 in magenta, and the D3 in orange. The ATF is shown in a ribbon diagram in cyan. (A) Molecular surface representation of the overall suPAR-ATF binding. The three uPAR domains form a conical cavity with a wide opening (25 Å) and large depth (14 Å) that are involved in the ATF binding. (B) Surface representation of the uPAR-ATF binding. The circled areas are regions 1 and 2 (from left to right) of uPAR-ATF interface. Oxygen atoms are shown in red, nitrogen atoms in blue, and sulfur in yellow. Waters involved in uPAR-ATF binding are shown as red spheres. Hydrogen bonds are shown as dashed lines (light blue). (C) Detailed interaction of suPAR (ribbon representation) and the ATF in stereoview. Thr8, Arg53, Glu68, Thr127, and His166 of suPAR form hydrogen bonds with Ser21, Lys23, Tyr24, Ser26, and Gln40 of ATF.
 
  The above figures are reprinted by permission from the AAAs: Science (2006, 311, 656-659) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21454081 M.D.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.  
20027185 H.W.Smith, and C.J.Marshall (2010).
Regulation of cell signalling by uPAR.
  Nat Rev Mol Cell Biol, 11, 23-36.  
20561148 J.Eugen-Olsen, O.Andersen, A.Linneberg, S.Ladelund, T.W.Hansen, A.Langkilde, J.Petersen, T.Pielak, L.N.Møller, J.Jeppesen, S.Lyngbaek, M.Fenger, M.H.Olsen, P.R.Hildebrandt, K.Borch-Johnsen, T.Jørgensen, and S.B.Haugaard (2010).
Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.
  J Intern Med, 268, 296-308.  
20010822 M.N.Wu, W.J.Joiner, T.Dean, Z.Yue, C.J.Smith, D.Chen, T.Hoshi, A.Sehgal, and K.Koh (2010).
SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker.
  Nat Neurosci, 13, 69-75.  
20872175 S.Greenberger, I.Adini, E.Boscolo, J.B.Mulliken, and J.Bischoff (2010).
Targeting NF-κB in infantile hemangioma-derived stem cells reduces VEGF-A expression.
  Angiogenesis, 13, 327-335.  
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.  
19354275 D.Liu, D.Overbey, L.Watkinson, and M.F.Giblin (2009).
Synthesis and characterization of an (111)In-labeled peptide for the in vivo localization of human cancers expressing the urokinase-type plasminogen activator receptor (uPAR).
  Bioconjug Chem, 20, 888-894.  
19389465 G.Theodorou, I.Bizelis, E.Rogdakis, and I.Politis (2009).
The ovine urokinase plasminogen activator and its receptor cDNAs: molecular cloning, characterization and expression in various tissues.
  Gene, 443, 158-169.  
18844213 I.Vocca, P.Franco, D.Alfano, G.Votta, M.V.Carriero, Y.Estrada, M.Caputi, P.A.Netti, L.Ossowski, and M.P.Stoppelli (2009).
Inhibition of migration and invasion of carcinoma cells by urokinase-derived antagonists of alphavbeta5 integrin activation.
  Int J Cancer, 124, 316-325.  
19383607 V.D'mello, S.Singh, Y.Wu, and R.B.Birge (2009).
The urokinase plasminogen activator receptor promotes efferocytosis of apoptotic cells.
  J Biol Chem, 284, 17030-17038.  
20025562 Z.Chen, L.Lin, Q.Huai, and M.Huang (2009).
Challenges for drug discovery - a case study of urokinase receptor inhibition.
  Comb Chem High Throughput Screen, 12, 961-967.  
18485004 A.Galat, G.Gross, P.Drevet, A.Sato, and A.Ménez (2008).
Conserved structural determinants in three-fingered protein domains.
  FEBS J, 275, 3207-3225.  
18718938 B.Royer-Zemmour, M.Ponsole-Lenfant, H.Gara, P.Roll, C.Lévêque, A.Massacrier, G.Ferracci, J.Cillario, A.Robaglia-Schlupp, R.Vincentelli, P.Cau, and P.Szepetowski (2008).
Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR.
  Hum Mol Genet, 17, 3617-3630.  
18500331 D.E.Klein, S.E.Stayrook, F.Shi, K.Narayan, and M.A.Lemmon (2008).
Structural basis for EGFR ligand sequestration by Argos.
  Nature, 453, 1271-1275.
PDB codes: 3c9a 3ca7 3cgu
18162327 K.Dass, A.Ahmad, A.S.Azmi, S.H.Sarkar, and F.H.Sarkar (2008).
Evolving role of uPA/uPAR system in human cancers.
  Cancer Treat Rev, 34, 122-136.  
17952591 M.Kotzsch, A.M.Sieuwerts, M.Grosser, A.Meye, S.Fuessel, M.E.Meijer-van Gelder, M.Smid, M.Schmitt, G.Baretton, T.Luther, V.Magdolen, and J.A.Foekens (2008).
Urokinase receptor splice variant uPAR-del4/5-associated gene expression in breast cancer: identification of rab31 as an independent prognostic factor.
  Breast Cancer Res Treat, 111, 229-240.  
18956887 O.A.Ozhogina, A.Grishaev, E.L.Bominaar, L.Patthy, M.Trexler, and M.Llinás (2008).
NMR solution structure of the neurotrypsin Kringle domain.
  Biochemistry, 47, 12290-12298.
PDB codes: 2k4r 2k51
18376415 Q.Huai, A.Zhou, L.Lin, A.P.Mazar, G.C.Parry, J.Callahan, D.E.Shaw, B.Furie, B.C.Furie, and M.Huang (2008).
Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes.
  Nat Struct Mol Biol, 15, 422-423.
PDB codes: 3bt1 3bt2
18495808 Y.Liu, D.J.Cao, I.M.Sainz, Y.L.Guo, and R.W.Colman (2008).
The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting the uPA-uPAR complex and inhibiting its signaling and internalization.
  Am J Physiol Cell Physiol, 295, C257-C267.  
17290405 B.S.Nielsen, F.Rank, M.Illemann, L.R.Lund, and K.Danø (2007).
Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor.
  Int J Cancer, 120, 2086-2095.  
17548516 C.D.Madsen, G.M.Ferraris, A.Andolfo, O.Cunningham, and N.Sidenius (2007).
uPAR-induced cell adhesion and migration: vitronectin provides the key.
  J Cell Biol, 177, 927-939.  
16878153 R.Mazzieri, F.Furlan, S.D'Alessio, E.Zonari, F.Talotta, P.Verde, and F.Blasi (2007).
A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts.
  Oncogene, 26, 725-732.  
17084931 V.Pillay, C.R.Dass, and P.F.Choong (2007).
The urokinase plasminogen activator receptor as a gene therapy target for cancer.
  Trends Biotechnol, 25, 33-39.  
17075310 S.Nozaki, Y.Endo, H.Nakahara, K.Yoshizawa, T.Ohara, and E.Yamamoto (2006).
Targeting urokinase-type plasminogen activator and its receptor for cancer therapy.
  Anticancer Drugs, 17, 1109-1117.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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