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Plasminogen activator PDB-id
1pk2
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Protein chain
90 a.a. *
Ligands
ACA

* Residue conservation analysis
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PDB id: 1pk2
Name: Plasminogen activator
Title: Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug

Structure:
Tissue-type plasminogen activator. Chain: a. Engineered: yes

Source:
Homo sapiens. Human. Organism_taxid: 9606

UniProt:
P00750 (TPA_HUMAN) Pfam   ArchSchema ?
Seq:
Struc:
Seq:
Struc:
Seq: 562 a.a.
Struc: 90 a.a.
Key:    PfamA domain
 Secondary structure  CATH domain

Enzyme class:
E.C.3.4.21.68   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:
Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.

Resolution:
not givenÅ

NMR structure:
1 models

Authors:
M.Llinas,I.-J.L.Byeon

Key ref:
I.J.Byeon and M.Llinás (1991). Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug.. J Mol Biol, 222, 1035-1051. [PubMed id: 1762144] [DOI: 10.1016/0022-2836(91)90592-T]

Date:
16-Sep-91

Release date:
31-Jan-94
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    Key reference    
 
 
DOI no: 10.1016/0022-2836(91)90592-T J Mol Biol 222:1035-1051 (1991)
PubMed id: 1762144  
 
 
Solution structure of the tissue-type plasminogen activator kringle 2 domain complexed to 6-aminohexanoic acid an antifibrinolytic drug.
I.J.Byeon, M.Llinás.
 
  ABSTRACT  
 
The solution structure of a recombinant tissue-type plasminogen activator kringle 2 domain, complexed with the antifibrinolytic drug 6-aminohexanoic acid (6-AHA) was determined via 1H nuclear magnetic resonance spectroscopy and dynamical simulated annealing calculations. The structure determination is based on 610 intramolecular kringle 2 and 14 intermolecular kringle 2-6-AHA interproton distance restraints, as well as on 82 torsion angle restraints. Three sets of simulated annealing structures were computed from three different classes of starting structures: (1) random conformations devoid of disulfide bridges; (2) random conformations that contain correct disulfide bonds; and (3) a folded conformation modeled after the homologous prothrombin kringle 1 X-ray crystallographic structure. All three sets of structures are well defined, with averaged atomic root-mean-square deviations between individual structures and mean set structures of 0.77, 0.99 and 0.70 A for backbone atoms, and 1.36, 1.55 and 1.41 A for all atoms, respectively. Kringle 2 is an oblate ellipsoid with overall dimensions of approximately 34 A x 30 A x 17 A. It exhibits a compact globular conformation characterized by a number of turns and loop elements as well as by one right-handed alpha-helix and five (1 extended and 4 rudimentary) antiparallel beta-sheets. The extended beta-sheet exhibits a right-handed twist. Close van der Waals' contacts between the Cys22-Cys63 and Cys51-Cys75 disulfide bridges and the central hydrophobic core composed of the Trp25, Leu46, His48a and Trp62 side-chains are among the distinguishing features of the kringle 2 fold. The binding site for 6-AHA appears as a rather exposed cleft with a negatively charged locus defined by the Asp55 and Asp57 side-chains, and with an aromatic pocket structured by the Tyr36, Trp62, His64 and Trp72 side-chains. The Trp62 and His64 rings line the back surface of the pocket, while the Tyr36 and Trp72 rings confine it from two sides. The Trp62 and Trp72 indole rings conform a V-shaped groove. The methyl groups of Val35 also contribute lipophilic character to the ligand-interacting surface. It is suggested that the positively charged side-chains of Lys34 and, potentially, Arg69 may favor interactions with the carboxylate group of the ligand. The Trp25 and Tyr74 aromatic rings, although conserved elements of the binding site structure, seem not to undergo direct contacts with the ligand.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17253978 J.Thompson, D.Fernandez-Reyes, L.Sharling, S.G.Moore, W.M.Eling, S.A.Kyes, C.I.Newbold, F.C.Kafatos, C.J.Janse, and A.P.Waters (2007).
Plasmodium cysteine repeat modular proteins 1-4: complex proteins with roles throughout the malaria parasite life cycle.
  Cell Microbiol, 9, 1466-1480.  
14717962 J.H.Geiger, and S.E.Cnudde (2004).
What the structure of angiostatin may tell us about its mechanism of action.
  J Thromb Haemost, 2, 23-34.  
11567102 O.A.Ozhogina, M.Trexler, L.Bányai, M.Llinás, and L.Patthy (2001).
Origin of fibronectin type II (FN2) modules: structural analyses of distantly-related members of the kringle family idey the kringle domain of neurotrypsin as a potential link between FN2 domains and kringles.
  Protein Sci, 10, 2114-2122.  
10625440 D.N.Marti, J.Schaller, and M.Llinás (1999).
Solution structure and dynamics of the plasminogen kringle 2-AMCHA complex: 3(1)-helix in homologous domains.
  Biochemistry, 38, 15741-15755.
PDB code: 1b2i
10428809 S.L.Nilsen, M.Prorok, and F.J.Castellino (1999).
Enhancement through mutagenesis of the binding of the isolated kringle 2 domain of human plasminogen to omega-amino acid ligands and to an internal sequence of a Streptococcal surface protein.
  J Biol Chem, 274, 22380-22386.  
10408340 Y.Chang, S.L.Nilsen, and F.J.Castellino (1999).
Functional and structural consequences of aromatic residue substitutions within the kringle-2 domain of tissue-type plasminogen activator.
  J Pept Res, 53, 656-664.  
9521645 Y.Chang, I.Mochalkin, S.G.McCance, B.Cheng, A.Tulinsky, and F.J.Castellino (1998).
Structure and ligand binding determinants of the recombinant kringle 5 domain of human plasminogen.
  Biochemistry, 37, 3258-3271.
PDB code: 5hpg
9305949 D.N.Marti, C.K.Hu, S.S.An, P.von Haller, J.Schaller, and M.Llinás (1997).
Ligand preferences of kringle 2 and homologous domains of human plasminogen: canvassing weak, intermediate, and high-affinity binding sites by 1H-NMR.
  Biochemistry, 36, 11591-11604.  
8652577 S.Söhndel, C.K.Hu, D.Marti, M.Affolter, J.Schaller, M.Llinás, and E.E.Rickli (1996).
Recombinant gene expression and 1H NMR characteristics of the kringle (2 + 3) supermodule: spectroscopic/functional individuality of plasminogen kringle domains.
  Biochemistry, 35, 2357-2364.  
7759476 A.H.Bakker, E.J.Weening-Verhoeff, and J.H.Verheijen (1995).
The role of the lysyl binding site of tissue-type plasminogen activator in the interaction with a forming fibrin clot.
  J Biol Chem, 270, 12355-12360.  
8307012 D.Marti, J.Schaller, B.Ochensberger, and E.E.Rickli (1994).
Expression, purification and characterization of the recombinant kringle 2 and kringle 3 domains of human plasminogen and analysis of their binding affinity for omega-aminocarboxylic acids.
  Eur J Biochem, 219, 455-462.  
8181475 M.R.Rejante, and M.Llinás (1994).
1H-NMR assignments and secondary structure of human plasminogen kringle 1.
  Eur J Biochem, 221, 927-937.  
8181476 M.R.Rejante, and M.Llinás (1994).
Solution structure of the epsilon-aminohexanoic acid complex of human plasminogen kringle 1.
  Eur J Biochem, 221, 939-949.
PDB codes: 1hpj 1hpk
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 code is shown on the right.