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PDBsum entry 1zg7
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References listed in PDB file
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Key reference
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Title
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Crystal structures of potent thiol-Based inhibitors bound to carboxypeptidase b.
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Authors
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M.Adler,
J.Bryant,
B.Buckman,
I.Islam,
B.Larsen,
S.Finster,
L.Kent,
K.May,
R.Mohan,
S.Yuan,
M.Whitlow.
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Ref.
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Biochemistry, 2005,
44,
9339-9347.
[DOI no: ]
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PubMed id
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Abstract
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This paper presents the crystal structure of porcine pancreatic carboxypeptidase
B (pp-CpB) in complex with a variety of thiol-based inhibitors that were
developed as antagonists of activated thrombin-activatable fibrinolysis
inhibitor (TAFIa). Recent studies have indicated that a selective inhibitor of
TAFIa could enhance the efficacy of existing thrombolytic agents for the
treatment of acute myocardial infarction, one of the most prevalent forms of
heart attacks. Unfortunately, activated TAFIa rapidly degrades in solution and
cannot be used for crystallographic studies. In contrast, porcine pancreatic CpB
is stable at room temperature and is available from commercial sources. Both
pancreatic CpB and TAFIa are zinc-based exopeptidases, and the proteins share a
47% sequence identity. The homology improves considerably in the active site
where nearly all of the residues are conserved. The inhibitors used in this
study were designed to mimic a C-terminal arginine residue, one of the natural
substrates of TAFIa. The X-ray structures show that the thiol group chelates the
active site zinc, the carboxylic acid forms a salt bridge to Arg145, and the
guanidine group forms two hydrogen bonds to Asp255. A meta-substituted phenyl
was introduced into our inhibitors to reduce conformational freedom. This
modification vastly improved the selectivity of compounds against other
exopeptidases that cleave basic residues. Comparisons between structures
indicate that selectivity derives from the interaction between the guanidine
group in the inhibitors and an acidic active site residue. The location of this
acidic residue is not conserved in the various carboxypeptidases.
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