Computational analysis of the domain architecture and substrate-gating mechanism of prolyl oligopeptidases from Shewanella woodyi and identification probable lead molecules

Abstract

Prolyl oligopeptidases (POP) are serine proteases found in prokaryotes and eukaryotes which hydrolyze the peptide bond containing proline. The current study focuses on the analysis of POP sequences, their distribution and domain architecture in Shewanella woodyi, a Gram negative, luminous bacterium which causes celiac sprue and similar infections in marine organisms. The POP undergoes huge inter-domain movement, which allows possible route for the entry of any substrate. Hence, it offers an opportunity to understand the mechanism of substrate gating by studying the domain architecture and possibility to identify a probable drug target. In the present study, the POP sequence was retrieved from GenBank data base and the best homologous templates were identified by PSI-BLAST search. The three dimensional structures of the closed and open forms of POP from Shewanella woodyi, which are not available in native form, was generated by homology modeling. The ideal lead molecules were screened by computer aided virtual screening and the binding potential of the best leads towards the target was studied by molecular docking. The domain architecture of the POP revealed that, it has a propeller domain consist of β-sheets, surrounded by α-helices and α/β hydrolase domain with catalytic triad containing Ser-564, Asp-646 and His-681. The hypothetical models of open and closed POP showed backbone RMSD value of 0.56 Å and 0.65 Å respectively. Ramachandran plot of the open and closed POP conformations accounts for 99.4% and 98.7% residues in the favoured region respectively. Our study revealed that, propeller domain comes as an insert between N-terminal and C-terminal α/β hydrolase domain. Molecular docking, drug likeliness properties and ADME prediction suggested that KUC-103481N and Pramiracetum can be used as probable lead molecules towards the POP from Shewanella woodyi.