A New Binding Site Involving the C-terminal Domain to Design Specific Inhibitors of PepX

Author(s): Joseph Andre, Mathieu Bach, Juan Xie, Pascal Rigolet.

Journal Name: Protein & Peptide Letters

Volume 20 , Issue 1 , 2013

Become EABM
Become Reviewer

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.

Keywords: X-prolyl dipeptidyl aminopeptidase, PepX, inhibitors, docking, family S15, streptococci, trypanosomes, enzyme activity, esterase, hydrolase, inhibitors

Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 1
Year: 2013
Page: [45 - 53]
Pages: 9
DOI: 10.2174/0929866511307010045

Article Metrics

PDF: 4