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http://hdl.handle.net/10261/201759
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dc.contributor.author | Bereta, Grzegorz | - |
dc.contributor.author | Goulas, Theodoros | - |
dc.contributor.author | Madej, Mariusz | - |
dc.contributor.author | Bielecka, Ewa | - |
dc.contributor.author | Solà, Maria | - |
dc.contributor.author | Potempa, Jan | - |
dc.contributor.author | Gomis-Rüth, F. Xavier | - |
dc.date.accessioned | 2020-02-24T13:59:28Z | - |
dc.date.available | 2020-02-24T13:59:28Z | - |
dc.date.issued | 2019-03 | - |
dc.identifier.citation | Protein Science 28(3): 478-486 (2019) | - |
dc.identifier.issn | 0961-8368 | - |
dc.identifier.uri | http://hdl.handle.net/10261/201759 | - |
dc.description.abstract | Citrullination 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 H236 (G231N/E232T/N235D) 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. Similar 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 1.6 Å‐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 G231N 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. | - |
dc.description.sponsorship | Fundació la Marató de TV3 201815; Grant sponsor: National Science Center, Poland UMO-2015/19/N/NZ1/00322 UMO-2018/29/N/NZ1/00992; Grant sponsor: National Government of Catalonia 2017SGR1192 2017SGR3; Grant sponsor: NIH/NIAID R01 DE022597; Grant sponsor: Spanish Ministry of Science, Innovation and Universities BFU2015-64487R BFU2015-70645R MDM-2014-0435. | - |
dc.language | eng | - |
dc.publisher | John Wiley & Sons | - |
dc.relation | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-64487-R | - |
dc.relation | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-70645-R | - |
dc.relation | info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2014-0435 | - |
dc.rights | closedAccess | - |
dc.subject | Bacterial virulence factor | - |
dc.subject | Citrullination | - |
dc.subject | Periodontal disease | - |
dc.subject | Rheumatoid arthritis | - |
dc.subject | Target–drug complex | - |
dc.subject | X‐ray crystal structure | - |
dc.title | Structure, function, and inhibition of a genomic/clinical variant of Porphyromonas gingivalis peptidylarginine deiminase | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1002/pro.3571 | - |
dc.relation.publisherversion | http://dx.doi.org/10.1002/pro.3571 | - |
dc.identifier.e-issn | 1469-896X | - |
dc.date.updated | 2020-02-24T13:59:28Z | - |
dc.contributor.funder | Fundació La Marató de TV3 | - |
dc.contributor.funder | National Science Centre (Poland) | - |
dc.contributor.funder | Generalitat de Catalunya | - |
dc.contributor.funder | National Institutes of Health (US) | - |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100004281 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100002809 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100000002 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100003329 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100008666 | es_ES |
dc.identifier.pmid | 30638292 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | No Fulltext | - |
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