6I9A

Porphyromonas gingivalis gingipain K (Kgp) in complex with inhibitor KYT-36

Summary for 6I9A

• Entry DOI: 10.2210/pdb6i9a/pdb
• Descriptor: Lys-gingipain W83, UNKNOWN ATOM OR ION, SODIUM ION, ... (9 entities in total)
• Functional Keywords: peptidase inhibitor, custeine peptidase, gingipain, periodontopathogen, periodontal disease, porphyromonas gingivalis, hydrolase
• Biological source: Porphyromonas gingivalis
• Total number of polymer chains: 2
• Total formula weight: 104814.70

Authors

Gomis-Ruth, F.X.,Guevara, T.,Rofdriguez-Banqueri, A. (deposition date: 2018-11-22, release date: 2019-03-13, Last modification date: 2024-01-24)

Primary citation

Guevara, T.,Rodriguez-Banqueri, A.,Lasica, A.M.,Ksiazek, M.,Potempa, B.A.,Potempa, J.,Gomis-Ruth, F.X.
Structural determinants of inhibition of Porphyromonas gingivalis gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor.
Sci Rep, 9:4935-4935, 2019

PubMed Abstract: Porphyromonas gingivalis is a member of the dysbiotic oral microbiome and a "keystone pathogen" that causes severe periodontal disease, which is among the most prevalent infectious diseases. Part of the virulence factors secreted by P. gingivalis are the essential cysteine peptidases gingipain K (Kgp) and R (RgpA and RgpB), which account for 85% of the extracellular proteolytic activity of the pathogen and are thus prime targets for inhibition. We report the high-resolution (1.20 Å) complex structure of Kgp with KYT-36, a peptide-derived, potent, bioavailable and highly selective inhibitor, which is widely used for studies in vitro, in cells and in vivo. Sub-nanomolar inhibition of Kgp is achieved by tight binding to the active-site cleft, which is covered for its sub-sites S through S' under establishment of nine hydrophobic interactions, 14 hydrogen bonds and one salt bridge. In addition, an inhibitor carbonyl carbon that mimics the scissile carbonyl of substrates is pyramidalized and just 2.02 Å away from the catalytic nucleophile of Kgp, CSγ. Thus, the crystal structure emulates a reaction intermediate of the first nucleophilic attack during catalysis of cysteine peptidases. The present study sets the pace for the development of tailored next-generation drugs to tackle P. gingivalis.

PubMed: 30894633
DOI: 10.1038/s41598-019-41354-3

Experimental method

X-RAY DIFFRACTION (1.2 Å)