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PDBsum entry 1bqy
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Hydrolase/hydrolase inhibitor
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PDB id
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1bqy
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Contents |
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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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The crystal structure of the novel snake venom plasminogen activator tsv-Pa: a prototype structure for snake venom serine proteinases.
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Authors
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M.A.Parry,
U.Jacob,
R.Huber,
A.Wisner,
C.Bon,
W.Bode.
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Ref.
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Structure, 1998,
6,
1195-1206.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Trimeresurus stejnejeri venom plasminogen activator (TSV-PA) is a
snake venom serine proteinase that specifically activates plasminogen. Snake
venom serine proteinases form a subfamily of trypsin-like proteinases that are
characterised by a high substrate specificity and resistance to inhibition. Many
of these venom enzymes specifically interfere with haemostatic mechanisms and
display a long circulating half-life. For these reasons several of them have
commercial applications and are potentially attractive pharmacological tools.
RESULTS: The crystal structure of TSV-PA has been determined to 2.5 A resolution
and refined to an R factor of 17.8 (R free, 24.4). The enzyme, showing the
overall polypeptide fold of trypsin-like serine proteinases, displays unique
structural elements such as the presence of a phenylalanine at position 193, a
C-terminal tail clamped via a disulphide bridge to the 99-loop, and a
structurally conserved Asp97 residue. The presence of a cis proline at position
218 is in agreement with evolutionary relationships to glandular kallikrein.
CONCLUSIONS: We postulate that Phe 193 accounts for the high substrate
specificity of TSV-PA and renders it incapable of forming a stable complex with
bovine pancreatic trypsin inhibitor and other extended substrates and
inhibitors. Mutational studies previously showed that Asp97 is crucial for the
plasminogenolytic activity of TSV-PA, here we identify the conservation of Asp97
in both types of mammalian plasminogen activator - tissue-type (tPA) and
urokinase-type (uPA). It seems likely that Asp97 of tPA and uPA will have a
similar role in plasminogen recognition. The C-terminal extension of TSV-PA is
conserved among snake venom serine proteinases, although its function is
unknown. The three-dimensional structure presented here is the first of a snake
venom serine proteinase and provides an excellent template for modelling other
homologous family members.
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Figure 2.
Figure 2. Stereoview superposition of Ca plots of the
catalytic domain of human tPA (blue), porcine glandular
kallikrein (yellow) and TSV-PA (red). The view and figure labels
are as in Figure 1 (standard orientation). The
chloromethylketone inhibitor (green) was added in the same
orientation as when bound to TSV-PA. (The figure was prepared
with MOLSCRIPT [51] and rendered using RASTER3D [52].)
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1998,
6,
1195-1206)
copyright 1998.
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