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

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Abstract
Gingipains are cysteine proteinases acting as key virulence factors of the bacterium Porphyromonas gingivalis , the major pathogen in periodontal disease. The 1.5 and 2.0 Å crystal structures of free and D‐Phe‐Phe‐Arg‐chloromethylketone‐inhibited gingipain R reveal a 435‐residue, single‐polypeptide chain organized into a catalytic and an immunoglobulin‐like domain. The catalytic domain is subdivided into two subdomains comprising four‐ and six‐stranded β‐sheets sandwiched by α‐helices. Each subdomain bears topological similarities to the p20‐p10 heterodimer of caspase‐1. The second subdomain harbours the Cys‐His catalytic diad and a nearby Glu arranged around the S1 specificity pocket, which carries an Asp residue to enforce preference for Arg‐P1 residues. This gingipain R structure is an excellent template for the rational design of drugs with a potential to cure and prevent periodontitis. Here we show the binding mode of an arginine‐containing inhibitor in the active‐site, thus identifying major interaction sites defining a suitable pharmacophor.