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PDBsum entry 2nwn
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References listed in PDB file
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Key reference
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Title
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Structural basis of specificity of a peptidyl urokinase inhibitor, Upain-1.
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Authors
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G.Zhao,
C.Yuan,
T.Wind,
Z.Huang,
P.A.Andreasen,
M.Huang.
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Ref.
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J Struct Biol, 2007,
160,
1-10.
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PubMed id
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Abstract
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Urokinase-type plasminogen activator (uPA) plays a crucial role in the
regulation of plasminogen activation, tumor cell adhesion and migration. The
inhibition of uPA activity is a promising mechanism for anti-cancer therapy. A
cyclic peptidyl inhibitor, upain-1, CSWRGLENHRMC, was identified recently as a
competitive and highly specific uPA inhibitor. We determined the crystal
structure of uPA in complex with upain-1 at 2.15 A. The structure reveals that
the cyclic peptide adopts a rigid conformation stabilized by a disulfide bond
(residues 1-12) and three tight beta turns (residues 3-6, 6-9, 9-12). The Glu7
residue of upain-1 forms hydrogen bonds with the main chain nitrogen atoms of
residues 4, 5, and 6 of upain-1, and is also critical for maintaining the active
conformation of upain-1. The Arg4 of upain-1 is inserted into the uPA's specific
S1 pocket. The Ser2 residue of upain-1 locates close to the S1beta pocket of
uPA. The Gly5 and Glu7 residues of upain-1 occupy the S2 pocket and the oxyanion
hole of uPA, respectively. Furthermore, the Asn8 residue of upain-1 binds to the
37- and 60-loops of uPA and renders the specificity of upain-1 for uPA. Based on
this structure, a new pharmacophore for the design of highly specific uPA
inhibitors was proposed.
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