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PDBsum entry 3dwc
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References listed in PDB file
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Key reference
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Title
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The molecular analysis of trypanosoma cruzi metallocarboxypeptidase 1 provides insight into fold and substrate specificity.
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Authors
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G.Niemirowicz,
D.Fernández,
M.Solà,
J.J.Cazzulo,
F.X.Avilés,
F.X.Gomis-Rüth.
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Ref.
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Mol Microbiol, 2008,
70,
853-866.
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PubMed id
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Abstract
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Trypanosoma cruzi is the aetiological agent of Chagas' disease, a chronic
infection that affects millions in Central and South America. Proteolytic
enzymes are involved in the development and progression of this disease and two
metallocarboxypeptidases, isolated from T. cruzi CL Brener clone, have recently
been characterized: TcMCP-1 and TcMCP-2. Although both are cytosolic and closely
related in sequence, they display different temporary expression patterns and
substrate preferences. TcMCP-1 removes basic C-terminal residues, whereas
TcMCP-2 prefers hydrophobic/aromatic residues. Here we report the
three-dimensional structure of TcMCP-1. It resembles an elongated cowry, with a
long, deep, narrow active-site cleft mimicking the aperture. It has an
N-terminal dimerization subdomain, involved in a homodimeric catalytically
active quaternary structure arrangement, and a proteolytic subdomain partitioned
by the cleft into an upper and a lower moiety. The cleft accommodates a
catalytic metal ion, most likely a cobalt, which is co-ordinated by residues
included in a characteristic zinc-binding sequence, HEXXH and a downstream
glutamate. The structure of TcMCP-1 shows strong topological similarity with
archaeal, bacterial and mammalian metallopeptidases including
angiotensin-converting enzyme, neurolysin and thimet oligopeptidase. A crucial
residue for shaping the S(1') pocket in TcMCP-1, Met-304, was mutated to the
respective residue in TcMCP-2, an arginine, leading to a TcMCP-1 variant with
TcMCP-2 specificity. The present studies pave the way for a better understanding
of a potential target in Chagas' disease at the molecular level and provide a
template for the design of novel therapeutic approaches.
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