title: The structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activity.
abstract: X-prolyl dipeptidyl aminopeptidases (X-PDAP) are enzymes catalysing the release of dipeptides from the amino termini of polypeptides containing a proline or an alanine at the penultimate position. Involved in various mammalian regulation processes, as well as in chronic human diseases, they have been proposed to play a role in pathogenicity for Streptococci. We compared the structure of X-PDAP from Lactococcus lactis (PepX) with its human counterpart DPP-IV. Despite very different overall folds, the residues most implicated for X-PDAP activity are conserved in the same positions and orientations in both enzymes, thus defining a structural signature for the X-PDAP specificity that crosses the species frontiers of evolution. Starting from this observation, we tested some inhibitors of DPP-IV on PepX activity, for which no specific inhibitor is known. We thus found that PepX was highly sensitive to valine-pyrrolidide with a KI of 9.3 microm, close to that reported in DPP-IV inhibition. We finally used the structure of PepX from L. lactis as a template for computer-based homology modeling of PepX from the pathogenic Streptococcus gordonii. Docking simulations of valine-pyrrolidide into the active site of PepX led to the identification of key residues for a rational drug design against PepX from Streptococci. These results could have applications in human health giving new perspectives to the struggle against pathogens.
authors.affiliation: Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquée CNRS, Ecole Normale Supérieure (ENS) Cachan, France. Pascal.Rigolet@lbpa.ens-cachan.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Rigolet
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Xi
authors.forename: Stephane
authors.initials: S
authors.lastname: Rety
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Chich
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry* / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D005057:Eukaryotic Cells / Q000201:enzymology; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D013294:Lactococcus lactis / Q000201:enzymology*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D013291:Streptococcus / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D058892:Adenosine Deaminase Inhibitors; D006023:Glycoproteins; D011480:Protease Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C098392:PepX dipeptidyl aminopeptidase; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase