Structural and biochemical characterization of a zinc metallopeptidase from Porphyromonas gingivalis.

Abstract

The pathogen Porphyromonas gingivalis contributes to the pathogenesis of periodontitis and other systemic diseases. The zinc-dependent metallopeptidase PepO is a virulence factor that plays a crucial role in the adhesion and invasion of Porphyromonas gingivalis to human cells. Here, we solved the 2.04 Å crystal structure of wild-type PepO in complex with the inhibitor phosphoramidon. The active-site pocket of PepO appears to exhibit an increased hydrophobicity and a more pronounced negative charge, highlighting distinct structural features compared to its homologs. In addition to phosphoramidon, several zinc metallopeptidase inhibitors, including thiorphan, omapatrilat, and sacubitrilat, exhibited varying degrees of inhibition on PepO enzymatic activity. Notably, the recombinant PepO showed distinct binding profiles to human fibrinogen, a characteristic that likely contributes to its role as virulence factors. These findings provide significant insights into the structural and functional mechanisms of PepO, offering a platform for the rational design of targeted inhibitors against the periodontal pathogen P. gingivalis.