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PDBsum entry 1nu7
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Hydrolase/hydrolase inhibitor
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PDB id
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1nu7
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Contents |
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28 a.a.
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258 a.a.
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282 a.a.
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27 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Staphylocoagulase is a prototype for the mechanism of cofactor-Induced zymogen activation.
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Authors
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R.Friedrich,
P.Panizzi,
P.Fuentes-Prior,
K.Richter,
I.Verhamme,
P.J.Anderson,
S.Kawabata,
R.Huber,
W.Bode,
P.E.Bock.
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Ref.
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Nature, 2003,
425,
535-539.
[DOI no: ]
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PubMed id
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Abstract
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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'.
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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.
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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.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2003,
425,
535-539)
copyright 2003.
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