Title:A New Binding Site Involving the C-terminal Domain to Design Specific Inhibitors of PepX
Volume: 20
Issue: 1
Author(s): Joseph Andre, Mathieu Bach, Juan Xie and Pascal Rigolet
Affiliation:
Keywords:
X-prolyl dipeptidyl aminopeptidase, PepX, inhibitors, docking, family S15, streptococci, trypanosomes, enzyme activity, esterase, hydrolase, inhibitors
Abstract: PepX is a X-prolyl dipeptidyl aminopeptidase of S15 family that cleaves dipeptides from the N-terminus of
polypeptides having a proline or alanine residue at the second position. Involved in bacterial nutrition and in peptide
maturation, this serine exopeptidase, counterpart of the mammalian DDP-4, has been proposed to play a role in pathogenicity
for Streptococci and to be a promising target against trypanosomes. Searching for specific inhibitors, we undertook
docking simulations on the whole surface of PepX from Lactococcus lactis, type example of the S15 family, which
revealed a new putative binding site in connection with the active site and involving the C-terminal domain. Accordingly
to the results of the computations, we synthesized two peptidomimetics of low molecular weight: the valinephenylpiperazine
and the valine-isopropylpiperazine that can accommodate to this putative binding site. Experiments revealed
that the valine-phenylpiperazine was an uncompetitive inhibitor whereas the valine-isopropylpiperazine showed to
be an activator of the enzyme activity. The valine-phenylpiperazine is interacting with ASN 379, GLU 383, GLU 474,
residues in connection with the specificity and active sites, and with the residues from the C-terminal domain LEU 693,
GLU 710 and GLN 712. These results point out a role of the C-terminal domain in controlling access to the active site of
enzymes of the S15 family, like PepX, the cocaine esterase or the alpha-amino acid ester hydrolase, and could have applications
in human health giving new perspectives to struggle against streptococci or trypanosomes by designing inhibitors
specific to the S15 family of enzymes.
