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PDBsum entry 1f5k
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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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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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Authors
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E.Zeslawska,
A.Schweinitz,
A.Karcher,
P.Sondermann,
S.Sperl,
J.Stürzebecher,
U.Jacob.
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Ref.
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J Mol Biol, 2000,
301,
465-475.
[DOI no: ]
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PubMed id
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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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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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