tailieunhanh - Báo cáo khoa học: The structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activity

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 mam-malian regulation processes, as well as in chronic human diseases, they have been proposed to play a role in pathogenicity forStreptococci. | iFEBS Journal The structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activity Pascal Rigolet1 Xu Guang Xi1 Stephane Rety1 and Jean-Francois Chich2 1 Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquee CNRS Ecole Normale Superieure ENS Cachan France 2 Virologie et Immunologie Moleculaires INRA Jouy-en-Josas France Keywords docking DPP-IV inhibitors PepX X-prolyl dipeptidyl aminopeptidase Correspondence P. Rigolet Laboratoire de Biotechnologies et Pharmacologie Genetique Appliquee CNRS Ecole Normale Superieure ENS Cachan 61 avenue du President Wilson 94235 Cachan cedex France Fax 33 1 47 40 76 71 Tel 33 1 47 40 68 76 E-mail Website http Received 21 January 2005 accepted 25 February 2005 doi 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 pM 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 .