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PDBsum entry 2pcu
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References listed in PDB file
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Key reference
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Title
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Caught after the act: a human a-Type metallocarboxypeptidase in a product complex with a cleaved hexapeptide.
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Authors
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A.Bayés,
D.Fernández,
M.Solà,
A.Marrero,
S.García-Piqué,
F.X.Avilés,
J.Vendrell,
F.X.Gomis-Rüth.
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Ref.
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Biochemistry, 2007,
46,
6921-6930.
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PubMed id
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Abstract
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A/B-type metallocarboxypeptidases (MCPs) are among the most thoroughly studied
proteolytic enzymes, and their catalytic mechanisms have been considered as
prototypes even for several unrelated metalloprote(in)ase families. It has long
been postulated that the nature of the side chains of at least five substrate
residues, i.e., P4-P1', influence Km and kcat and that once the peptide or
protein substrate is cleaved, both products remain in the first instance bound
to the active-site cleft of the enzyme in a double-product complex. Structural
details of binding of substrate to the nonprimed side of the cleft have largely
relied on complexes with protein inhibitors and peptidomimetic small-molecule
inhibitors that do not span the entire groove. In the former, the presence of
N-terminal globular protein domains participating in large-scale interactions
with the surface of the cognate catalytic domain outside the active-site cleft
mostly conditions the way their C-terminal tails bind to the cleft. Accordingly,
they may not be accurate models for a product complex. We hereby provide the
structural details of a true cleaved double-product complex with a hexapeptide
of an MCP engaged in prostate cancer, human carboxypeptidase A4, employing
diffraction data to 1.6 A resolution (Rcryst and Rfree = 0.159 and 0.176,
respectively). These studies provide detailed information about subsites S5-S1'
and contribute to our knowledge of the cleavage mechanism, which is revisited in
light of these new structural insights.
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