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Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling
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Rea, Dean, Van Elzen, Roos, De Winter, Hans, Van Goethem, Sebastiaan, Landuyt, Bart, Luyten, Walter, Schoofs, Liliane, Van Der Veken, Pieter, Augustyns, Koen, De Meester, Ingrid, Fülöp, Vilmos and Lambeir, Anne-Marie (2017) Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling. European Journal of Medicinal Chemistry, 139 . pp. 482-491. doi:10.1016/j.ejmech.2017.08.024 ISSN 0223-5234.
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Official URL: http://dx.doi.org/10.1016/j.ejmech.2017.08.024
Abstract
The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QR Microbiology R Medicine > RK Dentistry |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
| Library of Congress Subject Headings (LCSH): | Porphyromonas gingivalis, Periodontal disease | ||||||||
| Journal or Publication Title: | European Journal of Medicinal Chemistry | ||||||||
| Publisher: | Elsevier Masson | ||||||||
| ISSN: | 0223-5234 | ||||||||
| Official Date: | 20 October 2017 | ||||||||
| Dates: |
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| Volume: | 139 | ||||||||
| Page Range: | pp. 482-491 | ||||||||
| DOI: | 10.1016/j.ejmech.2017.08.024 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
| Date of first compliant deposit: | 1 November 2017 | ||||||||
| Date of first compliant Open Access: | 10 August 2018 | ||||||||
| Funder: | Fonds Wetenschappelijk Onderzoek (FWO), Agentschap voor Innovatie door Wetenschap en Technologie (Belgium) (IWT), Katholieke Universiteit te Leuven (1970- ), Seventh Framework Programme (European Commission) (FP7) | ||||||||
| Grant number: | Project code G.0173.09N (FWO), Grant SBO 50164, IOF/KP/09/003 (Katholieke Universiteit te Leuven (1970- )), EU-FP7 HEALTH-Proposal No. 223077 NEUROPRO (FP7) |
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