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PDBsum entry 5e3c
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References listed in PDB file
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Key reference
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Title
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Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.
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Authors
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P.Kumar,
V.Reithofer,
M.Reisinger,
S.Wallner,
T.Pavkov-Keller,
P.Macheroux,
K.Gruber.
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Ref.
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Sci Rep, 2016,
6,
23787.
[DOI no: ]
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PubMed id
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Abstract
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Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving
dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is
likely involved in a number of physiological processes such as nociception and
is also implicated in several forms of cancer. We present high-resolution
crystal structures of hDPP III in complex with opioid peptides (Met-and
Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide
inhibitor IVYPW. These structures confirm the previously reported large
conformational change of the enzyme upon ligand binding and show that the
structure of the closed conformation is independent of the nature of the bound
peptide. The overall peptide-binding mode is also conserved ensuring the correct
positioning of the scissile peptide bond with respect to the catalytic zinc ion.
The structure of the angiotensin-II complex shows, how longer peptides are
accommodated in the binding cleft of hDPP III. Differences in the binding modes
allow a distinction between real substrates and inhibitory peptides or
"slow" substrates. The latter displace a zinc bound water molecule
necessitating the energetically much less favoured anhydride mechanism as
opposed to the favoured promoted-water mechanism. The structural data also form
the necessary framework for the design of specific hDPP III inhibitors.
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