Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold

Gingipains are cysteine proteinases acting as key virulence factors of the bacterium Porphyromonas gingivalis, the major pathogen in periodontal disea se. The 1.5 and 2.0 Angstrom crystal structures of free and D-Phe-Phe-Arg-c hloromethylketone-inhibited gingipain R reveal a 435-residue, single-polype ptide chain organized into a catalytic and an immunoglobulin-like domain. T he catalytic domain is subdivided into two subdomains comprising four- and six-stranded beta-sheets sandwiched by alpha-helices, Each subdomain bears topological similarities to the p20-p10 heterodimer of caspase-1. The secon d subdomain harbours the Cys-His catalytic diad and a nearby Glu arranged a round the S1 specificity pocket, which carries an Asp residue to enforce pr eference for Arg-P1 residues. This gingipain R structure is an excellent te mplate for the rational design of drugs with a potential to cure and preven t periodontitis. Here we show the binding mode of an arginine-containing in hibitor in the active-site, thus identifying major interaction sites defini ng a suitable pharmacophor.