6i0x
From Proteopedia
Porphyromonas gingivalis peptidylarginine deminase (PPAD) mutant G231N/E232T/N235D in complex with Cl-amidine.
Structural highlights
FunctionPAD_PORGI Deiminates the guanidino group of C-terminal arginine residues on a variety of peptides, including the vasoregulatory peptide-hormone bradykinin, to yield ammonia and a citrulline residue. May promote the growth of the pathogen in the periodontal pocket by producing ammonia, ammonia having a protective effect during acidic cleaning cycles in the mouth.[1] Publication Abstract from PubMedCitrullination is an essential post-translational modification in which the guanidinium group of protein and peptide arginines is deiminated by peptidylarginine deiminases (PADs). When deregulated, excessive citrullination leads to inflammation as in severe periodontal disease (PD) and rheumatoid arthritis (RA). Porphyromonas gingivalis is the major periodontopathogenic causative agent of PD and also an etiological agent of RA. It secretes a PAD, termed Porphyromonas PAD (PPAD), which is a virulence factor that causes aberrant citrullination. Analysis of P. gingivalis genomes of laboratory strains and clinical isolates unveiled a PPAD variant (PPAD-T2), which showed three amino-acid substitutions directly preceding catalytic residue H(236) (G(231) N/E(232) T/N(235) D) when compared with PPAD from the reference strain (PPAD-T1). Mutation of these positions in the reference strain resulted in twofold higher cell-associated citrullinating activity. Similarly to PPAD-T1, recombinant PPAD-T2 citrullinated arginines at the C-termini of general peptidic substrates but not within peptides. Catalytically, PPAD-T2 showed weaker substrate binding but higher turnover rates than PPAD-T1. In contrast, no differences were found in thermal stability. The 1.6A-resolution X-ray crystal structure of PPAD-T2 in complex with the general human PAD inhibitor, Cl-amidine, revealed that the inhibitor moiety is tightly bound and that mutations localize to a loop engaged in substrate/inhibitor binding. In particular, mutation G(231) N caused a slight structural rearrangement, which probably originated the higher substrate turnover observed. The present data compare two natural PPAD variants and will set the pace for the design of specific inhibitors against P. gingivalis-caused PD. This article is protected by copyright. All rights reserved. Structure, function and inhibition of a genomic/clinical variant of Porphyromonas gingivalis peptidylarginine deiminase.,Bereta G, Goulas T, Madej M, Bielecka E, Sola M, Potempa J, Gomis-Ruth FX Protein Sci. 2019 Jan 14. doi: 10.1002/pro.3571. PMID:30638292[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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