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PDBsum entry 1w10
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.21.73
- u-plasminogen activator.
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Reaction:
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Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.
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J Mol Biol
328:109-118
(2003)
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PubMed id:
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Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors.
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E.Zeslawska,
U.Jacob,
A.Schweinitz,
G.Coombs,
W.Bode,
E.Madison.
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ABSTRACT
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Urokinase type plasminogen activator (uPA), a trypsin-like serine proteinase,
plays an important role in normal tissue re-modelling, cell adhesion, and cell
motility. In addition, studies utilizing normal animals and potent, selective
uPA inhibitors or genetically modified mice that lack functional uPA genes have
demonstrated that uPA can significantly enhance tumor initiation, growth,
progression and metastasis, strongly suggesting that this enzyme may be a
promising anti-cancer target. We have investigated the structure-activity
relationship (SAR) of peptidomimetic inhibitors of uPA and solved high
resolution X-ray structures of key, lead small molecule inhibitors (e.g.
phenethylsulfonamidino(P4)-D-seryl(P3)-L-alanyl(P2)-L-argininal(P1) and
derivatives thereof) in complex with the uPA proteinase domain. These potent
inhibitors are highly selective for uPA. The non-natural D-seryl residue present
at the P3 position in these inhibitors contributes substantially to both potency
and selectivity because, due to its D-configuration, its side-chain binds in the
S4 pocket to interact with the uPA unique residues Leu97b and His99. Additional
potency and selectivity can be achieved by optimizing the inhibitor P4 residue
to bind a pocket, known as S1sub or S1beta, that is adjacent to the primary
specificity pocket of uPA.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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M.Hansen,
T.Wind,
G.E.Blouse,
A.Christensen,
H.H.Petersen,
S.Kjelgaard,
L.Mathiasen,
T.L.Holtet,
and
P.A.Andreasen
(2005).
A urokinase-type plasminogen activator-inhibiting cyclic peptide with an unusual P2 residue and an extended protease binding surface demonstrates new modalities for enzyme inhibition.
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J Biol Chem,
280,
38424-38437.
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Z.Sun,
and
J.N.Liu
(2005).
Mutagenesis at Pro309 of single-chain urokinase-type plasminogen activator alters its catalytic properties.
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Proteins,
61,
870-877.
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A.Schweinitz,
T.Steinmetzer,
I.J.Banke,
M.J.Arlt,
A.Stürzebecher,
O.Schuster,
A.Geissler,
H.Giersiefen,
E.Zeslawska,
U.Jacob,
A.Krüger,
and
J.Stürzebecher
(2004).
Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents.
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J Biol Chem,
279,
33613-33622.
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PDB codes:
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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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Links
