title: Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold.
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 A 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 beta-sheets sandwiched by alpha-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.
authors.affiliation: Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, D-82152 Martinsried, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Eichinger
authors.forename: H G
authors.initials: HG
authors.lastname: Beisel
authors.forename: U
authors.initials: U
authors.lastname: Jacob
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.forename: F J
authors.initials: FJ
authors.lastname: Medrano
authors.forename: A
authors.initials: A
authors.lastname: Banbula
authors.forename: J
authors.initials: J
authors.lastname: Potempa
authors.forename: J
authors.initials: J
authors.lastname: Travis
authors.forename: W
authors.initials: W
authors.lastname: Bode
mesh_terms: D018829:Adhesins, Bacterial; D000595:Amino Acid Sequence; D020169:Caspases / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010510:Periodontal Diseases / Q000209:etiology; D016966:Porphyromonas gingivalis / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D014774:Virulence
chemical_list: D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins; D007136:Immunoglobulins; D020169:Caspases; D003546:Cysteine Endopeptidases