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PDBsum entry 1nu7
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Hydrolase/hydrolase inhibitor PDB id
1nu7

 

 

 

 

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Contents
Protein chains
28 a.a.
258 a.a. *
282 a.a. *
27 a.a. *
Ligands
0ZJ ×2
IMD ×6
Metals
_HG ×4
Waters ×748
* Residue conservation analysis
PDB id:
1nu7
Name: Hydrolase/hydrolase inhibitor
Title: Staphylocoagulase-thrombin complex
Structure: Thrombin light chain. Chain: a, e. Fragment: unp residues 332-359. Synonym: coagulation factor ii. Thrombin heavy chain. Chain: b, f. Fragment: unp residues 364-622. Synonym: coagulation factor ii. Staphylocoagulase.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Staphylococcus aureus. Organism_taxid: 1280. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Biol. unit: 60mer (from PQS)
Resolution:
2.20Å     R-factor:   0.209     R-free:   0.249
Authors: R.Friedrich,W.Bode,P.Fuentes-Prior,P.Panizzi,P.E.Bock
Key ref:
R.Friedrich et al. (2003). Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature, 425, 535-539. PubMed id: 14523451 DOI: 10.1038/nature01962
Date:
31-Jan-03     Release date:   07-Oct-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
28 a.a.
Protein chains
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
258 a.a.
Protein chains
Pfam   ArchSchema ?
Q846V4  (Q846V4_STAAU) -  Staphylocoagulase (Fragment) from Staphylococcus aureus
Seq:
Struc: 		 
Seq:
Struc: 		660 a.a.
282 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
27 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, E, F: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
DOI no: 10.1038/nature01962 Nature 425:535-539 (2003)
PubMed id: 14523451  
 
 
Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation.
R.Friedrich, P.Panizzi, P.Fuentes-Prior, K.Richter, I.Verhamme, P.J.Anderson, S.Kawabata, R.Huber, W.Bode, P.E.Bock.
 
  ABSTRACT  
 
Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. Here we present the 2.2 A crystal structures of human alpha-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as 'molecular sexuality'.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: a, Human prothrombin and its cofactor SC. Cleavage sites in the latter are indicated by arrowheads. b, SC homologues: CAD46494 (refs 8, 9); FbpA, fibrinogen-binding protein A (ref 22); NP_687847; SfbX, Streptococcus pyogenes fibronectin (FN)-binding protein (ref 23); and vWbp (ref 7). The sequence that directs cell-wall sorting of SfbX is indicated by a diamond; the RGD triplet is also indicated. Gla, gamma-carboxyglutamic acid domain; K, kringle domain; L, light chain; C, cytoplasmic tail; D1/D2, alpha-helical domains; Fn, FN-binding repeats (refs 24,25); M, membrane-spanning peptide; P/S, proline/serine-rich region; R, SC C-terminal repeats; RL4, domain homologous to the large ribosomal subunit L4; S, signal sequence. 		Figure 2.
Figure 2: Structure of the human alpha--thrombin Met-SC(1 -325) complex. Ribbon plot showing the symmetric dimer in the asymmetric unit. Thrombin is shown in yellow and gold; SC is shown in red and salmon. The side chains of thrombin's active-site residues are shown with all non-hydrogen atoms and are circled in blue. Both monomers are related by an exact but crystallographically 'local' two-fold rotation axis.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 425, 535-539) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21353779 A.G.Cheng, A.C.Dedent, O.Schneewind, and D.Missiakas (2011).
A play in four acts: Staphylococcus aureus abscess formation.
  Trends Microbiol, 19, 225-232.  
21326199 T.Clausen, M.Kaiser, R.Huber, and M.Ehrmann (2011).
HTRA proteases: regulated proteolysis in protein quality control.
  Nat Rev Mol Cell Biol, 12, 152-162.  
20700445 A.G.Cheng, M.McAdow, H.K.Kim, T.Bae, D.M.Missiakas, and O.Schneewind (2010).
Contribution of coagulases towards Staphylococcus aureus disease and protective immunity.
  PLoS Pathog, 6, 0.  
20143368 C.Ottmann, P.Hauske, and M.Kaiser (2010).
Activation instead of inhibition: targeting proenzymes for small-molecule intervention.
  Chembiochem, 11, 637-639.  
20581825 T.Krojer, J.Sawa, R.Huber, and T.Clausen (2010).
HtrA proteases have a conserved activation mechanism that can be triggered by distinct molecular cues.
  Nat Struct Mol Biol, 17, 844-852.
PDB codes: 3mh4 3mh5 3mh6 3mh7
20974933 Z.Chen, L.A.Pelc, and E.Di Cera (2010).
Crystal structure of prethrombin-1.
  Proc Natl Acad Sci U S A, 107, 19278-19283.
PDB code: 3nxp
19180666 E.Di Cera (2009).
Serine proteases.
  IUBMB Life, 61, 510-515.  
19416890 H.K.Kroh, P.Panizzi, and P.E.Bock (2009).
Von Willebrand factor-binding protein is a hysteretic conformational activator of prothrombin.
  Proc Natl Acad Sci U S A, 106, 7786-7791.  
19630791 J.A.Huntington (2009).
Slow thrombin is zymogen-like.
  J Thromb Haemost, 7, 159-164.  
20004165 R.Ganesan, C.Eigenbrot, Y.Wu, W.C.Liang, S.Shia, M.T.Lipari, and D.Kirchhofer (2009).
Unraveling the allosteric mechanism of serine protease inhibition by an antibody.
  Structure, 17, 1614-1624.
PDB codes: 2wub 2wuc 3k2u
19492076 S.Watanabe, T.Ito, T.Sasaki, S.Li, I.Uchiyama, K.Kishii, K.Kikuchi, R.L.Skov, and K.Hiramatsu (2009).
Genetic diversity of staphylocoagulase genes (coa): insight into the evolution of variable chromosomal virulence factors in Staphylococcus aureus.
  PLoS One, 4, e5714.  
18988866 T.H.Yun, J.E.Cott, R.I.Tapping, J.M.Slauch, and J.H.Morrissey (2009).
Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins.
  Blood, 113, 1139-1148.  
18404270 A.Muhlia-Almazán, A.Sánchez-Paz, and F.L.García-Carreño (2008).
Invertebrate trypsins: a review.
  J Comp Physiol [B], 178, 655-672.  
19021141 P.Hauske, C.Ottmann, M.Meltzer, M.Ehrmann, and M.Kaiser (2008).
Allosteric regulation of proteases.
  Chembiochem, 9, 2920-2928.  
17372204 D.Kirchhofer, M.T.Lipari, L.Santell, K.L.Billeci, H.R.Maun, W.N.Sandoval, P.Moran, J.Ridgway, C.Eigenbrot, and R.A.Lazarus (2007).
Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist.
  Proc Natl Acad Sci U S A, 104, 5306-5311.  
17635705 J.L.Degen, T.H.Bugge, and J.D.Goguen (2007).
Fibrin and fibrinolysis in infection and host defense.
  J Thromb Haemost, 5, 24-31.  
17878159 N.N.Nickerson, L.Prasad, L.Jacob, L.T.Delbaere, and M.J.McGavin (2007).
Activation of the SspA serine protease zymogen of Staphylococcus aureus proceeds through unique variations of a trypsinogen-like mechanism and is dependent on both autocatalytic and metalloprotease-specific processing.
  J Biol Chem, 282, 34129-34138.  
17635714 P.E.Bock, P.Panizzi, and I.M.Verhamme (2007).
Exosites in the substrate specificity of blood coagulation reactions.
  J Thromb Haemost, 5, 81-94.  
16699514 E.Papagrigoriou, P.A.McEwan, P.N.Walsh, and J.Emsley (2006).
Crystal structure of the factor XI zymogen reveals a pathway for transactivation.
  Nat Struct Mol Biol, 13, 557-558.
PDB code: 2f83
16230340 P.Panizzi, R.Friedrich, P.Fuentes-Prior, H.K.Kroh, J.Briggs, G.Tans, W.Bode, and P.E.Bock (2006).
Novel fluorescent prothrombin analogs as probes of staphylocoagulase-prothrombin interactions.
  J Biol Chem, 281, 1169-1178.  
16230339 P.Panizzi, R.Friedrich, P.Fuentes-Prior, K.Richter, P.E.Bock, and W.Bode (2006).
Fibrinogen substrate recognition by staphylocoagulase.(pro)thrombin complexes.
  J Biol Chem, 281, 1179-1187.  
16230338 R.Friedrich, P.Panizzi, S.Kawabata, W.Bode, P.E.Bock, and P.Fuentes-Prior (2006).
Structural basis for reduced staphylocoagulase-mediated bovine prothrombin activation.
  J Biol Chem, 281, 1188-1195.
PDB code: 2a1d
16006504 E.P.Bianchini, S.J.Orcutt, P.Panizzi, P.E.Bock, and S.Krishnaswamy (2005).
Ratcheting of the substrate from the zymogen to proteinase conformations directs the sequential cleavage of prothrombin by prothrombinase.
  Proc Natl Acad Sci U S A, 102, 10099-10104.  
15501819 N.A.Copeland, and C.Kleanthous (2005).
The role of an activating peptide in protease-mediated suicide of Escherichia coli K12.
  J Biol Chem, 280, 112-117.  
15623524 R.R.Bean, I.M.Verhamme, and P.E.Bock (2005).
Role of the streptokinase alpha-domain in the interactions of streptokinase with plasminogen and plasmin.
  J Biol Chem, 280, 7504-7510.  
15901693 S.Watanabe, T.Ito, F.Takeuchi, M.Endo, E.Okuno, and K.Hiramatsu (2005).
Structural comparison of ten serotypes of staphylocoagulases in Staphylococcus aureus.
  J Bacteriol, 187, 3698-3707.  
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
15152000 A.O.Pineda, C.J.Carrell, L.A.Bush, S.Prasad, S.Caccia, Z.W.Chen, F.S.Mathews, and E.Di Cera (2004).
Molecular dissection of Na+ binding to thrombin.
  J Biol Chem, 279, 31842-31853.
PDB codes: 1sfq 1sg8 1sgi 1shh
15137941 C.Wilken, K.Kitzing, R.Kurzbauer, M.Ehrmann, and T.Clausen (2004).
Crystal structure of the DegS stress sensor: How a PDZ domain recognizes misfolded protein and activates a protease.
  Cell, 117, 483-494.
PDB codes: 1sot 1soz 1vcw
15135538 J.Bjerketorp, K.Jacobsson, and L.Frykberg (2004).
The von Willebrand factor-binding protein (vWbp) of Staphylococcus aureus is a coagulase.
  FEMS Microbiol Lett, 234, 309-314.  
15568990 M.Ehrmann, and T.Clausen (2004).
Proteolysis as a regulatory mechanism.
  Annu Rev Genet, 38, 709-724.  
15558209 P.Panizzi, R.Friedrich, P.Fuentes-Prior, W.Bode, and P.E.Bock (2004).
The staphylocoagulase family of zymogen activator and adhesion proteins.
  Cell Mol Life Sci, 61, 2793-2798.  
15211511 S.Terzyan, N.Wakeham, P.Zhai, K.Rodgers, and X.C.Zhang (2004).
Characterization of Lys-698-to-Met substitution in human plasminogen catalytic domain.
  Proteins, 56, 277-284.
PDB code: 1rjx
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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