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PDBsum entry 1f5k
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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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DOI no:
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J Mol Biol
301:465-475
(2000)
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PubMed id:
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Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design.
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E.Zeslawska,
A.Schweinitz,
A.Karcher,
P.Sondermann,
S.Sperl,
J.Stürzebecher,
U.Jacob.
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ABSTRACT
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Urokinase is a serine protease involved in cancer growth and metastasis. Here we
present the first urokinase crystal structure in complex with reversible
inhibitors at 2.1 and 2.6 A resolution. These inhibitor complex structures have
been obtained from crystals of engineered urokinase type plasminogen activator
designed to obtain a crystal form open for inhibitor soaking. The mutant C122S
loses its flexible A-chain upon activation cleavage and crystallizes in the
presence of benzamidine, which was later displaced by the desired inhibitor.
This new soakable crystal form turned out to be of great value in the process of
structure-based drug design. The evaluated binding mode of amiloride, and UKI-1D
revealed a new subsite of the primary specificity pocket of urokinase that will
be employed in the future ligand optimisation process.
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Selected figure(s)
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Figure 4.
Figure 4. Binding mode of the inhibitors (a) UKI-1D (b)
amiloride and (c) WX293T (all in white) in complex with bc-uPA
(in yellow) in ball-and-stick representation. Hydrogen bonds are
drawn as thin white lines and the chlorine atom is depicted in
green. The Figure was produced with MOLSCRIPT and Raster3D.
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Figure 5.
Figure 5. Close-up of the active site of urokinase, in
ball-and-stick representation, covered by a semi-transparent
surface coloured according to the surface electrostatic
potential from negative (red) to positive (blue). Also shown is
a superposition of amiloride (magenta), EGR-cmk (yellow) and
WX293T (cyan) in ball-and-stick representation occupying the
different accessible subsites as indicated and discussed in the
text. The Figure was produced with MOLSCRIPT, Raster3D and GRASP
[Nicholls et al 1991].
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2000,
301,
465-475)
copyright 2000.
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Figures were
selected
by an automated process.
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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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A.L.Brown,
S.M.Fernandez-Illescas,
Z.Liao,
and
M.B.Goodman
(2007).
Gain-of-function mutations in the MEC-4 DEG/ENaC sensory mechanotransduction channel alter gating and drug blockade.
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J Gen Physiol,
129,
161-173.
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O.J.Kyrieleis,
R.Huber,
E.Ong,
R.Oehler,
M.Hunter,
E.L.Madison,
and
U.Jacob
(2007).
Crystal structure of the catalytic domain of DESC1, a new member of the type II transmembrane serine proteinase family.
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FEBS J,
274,
2148-2160.
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PDB code:
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E.Atkins,
S.Zamora,
B.J.Candia,
A.Baca,
and
R.A.Orlando
(2005).
Development of a Mammalian suspension culture for expression of active recombinant human urokinase-type plasminogen activator.
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Cytotechnology,
49,
25-37.
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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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O.B.Kashlan,
S.Sheng,
and
T.R.Kleyman
(2005).
On the interaction between amiloride and its putative alpha-subunit epithelial Na+ channel binding site.
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J Biol Chem,
280,
26206-26215.
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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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M.M.Mueller,
S.Sperl,
J.Stürzebecher,
W.Bode,
and
L.Moroder
(2002).
(R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
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Biol Chem,
383,
1185-1191.
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PDB codes:
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B.A.Katz,
P.A.Sprengeler,
C.Luong,
E.Verner,
K.Elrod,
M.Kirtley,
J.Janc,
J.R.Spencer,
J.G.Breitenbucher,
H.Hui,
D.McGee,
D.Allen,
A.Martelli,
and
R.L.Mackman
(2001).
Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets.
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Chem Biol,
8,
1107-1121.
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PDB codes:
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B.Muehlenweg,
S.Sperl,
V.Magdolen,
M.Schmitt,
and
N.Harbeck
(2001).
Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours.
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Expert Opin Biol Ther,
1,
683-691.
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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
code is
shown on the right.
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Links
