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PDBsum entry 4x0w
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Hydrolase inhibitor/hydrolase
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PDB id
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4x0w
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References listed in PDB file
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Key reference
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Title
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Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-Type plasminogen activator with isomeric p1 residues.
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Authors
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L.Jiang,
B.Zhao,
P.Xu,
H.P.Sørensen,
J.K.Jensen,
A.Christensen,
M.Hosseini,
N.C.Nielsen,
K.J.Jensen,
P.A.Andreasen,
M.Huang.
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Ref.
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Int J Biochem Cell Biol, 2015,
62,
88-92.
[DOI no: ]
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PubMed id
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Abstract
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Two isomeric piperidine derivatives (meta and para isomers) were used as
arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC)
of urokinase-type plasminogen activator. The two resulting cyclic peptides
showed vastly different affinities (∼70 fold) to the target enzyme. X-ray
crystal structure analysis showed that the two P1 residues were inserted into
the S1 specificity pocket in indistinguishable manners. However, the rest of the
peptides bound in entirely different ways on the surface of the enzyme, and the
two peptides have different conformations, despite the highly similar sequence.
These results demonstrate how the subtle difference in P1 residue can dictate
the exosite interactions and the potencies of peptidic inhibitors, and highlight
the importance of the P1 residue for protease inhibition. This study provides
important information for the development of peptidic agents for pharmacological
intervention.
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