4rbm
Porphyromonas gingivalis gingipain K (Kgp) catalytic and immunoglobulin superfamily-like domains
Structural highlights
FunctionKGP83_PORGN Cysteine proteinase with a strong preference for substrates with Lys in the P1 position. Hydrolyzes bovine hemoglobin, bovine serum albumin, casein, human placental type I collagen and human IgA and IgG. Disrupts the functions of polymorphonuclear leukocytes. May act as a virulence factor in the development of peridontal disease. Involved in the coaggregation of P.gingivalis with other oral bacteria (By similarity).[UniProtKB:B2RLK2] Publication Abstract from PubMedCysteine peptidases are key proteolytic virulence factors of the periodontopathogen Porphyromonas gingivalis, which causes chronic periodontitis, the most prevalent dysbiosis-driven disease in humans. Two peptidases, gingipain K (Kgp) and R (RgpA and RgpB), which differ in their selectivity after lysines and arginines, respectively, collectively account for 85% of the extracellular proteolytic activity of P. gingivalis at the site of infection. Therefore, they are promising targets for the design of specific inhibitors. While the structure of mature RgpB is known, little is known about Kgp, which shares only 27% sequence identity. We report the high-resolution crystal structure of a competent fragment of Kgp encompassing the catalytic cysteine peptidase domain and a downstream immunoglobulin superfamily-like domain, which is required for folding and secretion of Kgp in vivo. The structure, which strikingly resembles a tooth, was serendipitously trapped with a fragment of a covalent inhibitor targeting the catalytic cysteine. This provided accurate insight into the active site and suggested that catalysis may require a catalytic triad, C477-H444-D388, rather than the cysteine-histidine dyad normally found in cysteine peptidases. In addition, a 20A-long solvent-filled interior channel traverses the molecule and links the bottom of the specificity pocket with the molecular surface opposite the active-site cleft. This channel, absent in RgpB, may enhance the plasticity of the enzyme, which would explain the much lower activity in vitro towards comparable specific synthetic substrates. Overall, the present results report the architecture and molecular determinants of the working mechanism of Kgp, including interaction with its substrates. Structure and mechanism of cysteine peptidase Kgp, a major virulence factor of Porphyromonas gingivalis in periodontitis.,de Diego I, Veillard F, Sztukowska M, Guevara T, Potempa B, Pomowski A, Huntington JA, Potempa J, Gomis-Ruth FX J Biol Chem. 2014 Sep 29. pii: jbc.M114.602052. PMID:25266723[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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