| Structural highlights
Function
DPP11_PORG3 Catalyzes the removal of dipeptides from the N-terminus of oligopeptides. Shows a strict specificity for acidic residues (Asp or Glu) in the P1 position, and has a hydrophobic residue preference at the P2 position. Preferentially cleaves the synthetic substrate Leu-Asp-methylcoumaryl-7-amide (Leu-Asp-MCA) as compared to Leu-Glu-MCA. Is involved in amino acid metabolism and bacterial growth of asaccharolytic P.gingivalis, that utilizes amino acids from extracellular proteinaceous nutrients as energy and carbon sources.[1] [2]
Publication Abstract from PubMed
Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.
Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase.,Sakamoto Y, Suzuki Y, Nakamura A, Watanabe Y, Sekiya M, Roppongi S, Kushibiki C, Iizuka I, Tani O, Sakashita H, Inaka K, Tanaka H, Yamada M, Ohta K, Honma N, Shida Y, Ogasawara W, Nakanishi-Matsui M, Nonaka T, Gouda H, Tanaka N Sci Rep. 2019 Sep 19;9(1):13587. doi: 10.1038/s41598-019-49984-3. PMID:31537874[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ohara-Nemoto Y, Shimoyama Y, Kimura S, Kon A, Haraga H, Ono T, Nemoto TK. Asp- and Glu-specific novel dipeptidyl peptidase 11 of Porphyromonas gingivalis ensures utilization of proteinaceous energy sources. J Biol Chem. 2011 Nov 4;286(44):38115-27. doi: 10.1074/jbc.M111.278572. Epub 2011, Sep 6. PMID:21896480 doi:http://dx.doi.org/10.1074/jbc.M111.278572
- ↑ Rouf SM, Ohara-Nemoto Y, Hoshino T, Fujiwara T, Ono T, Nemoto TK. Discrimination based on Gly and Arg/Ser at position 673 between dipeptidyl-peptidase (DPP) 7 and DPP11, widely distributed DPPs in pathogenic and environmental gram-negative bacteria. Biochimie. 2013 Apr;95(4):824-32. doi: 10.1016/j.biochi.2012.11.019. Epub 2012, Dec 12. PMID:23246913 doi:http://dx.doi.org/10.1016/j.biochi.2012.11.019
- ↑ Sakamoto Y, Suzuki Y, Nakamura A, Watanabe Y, Sekiya M, Roppongi S, Kushibiki C, Iizuka I, Tani O, Sakashita H, Inaka K, Tanaka H, Yamada M, Ohta K, Honma N, Shida Y, Ogasawara W, Nakanishi-Matsui M, Nonaka T, Gouda H, Tanaka N. Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase. Sci Rep. 2019 Sep 19;9(1):13587. doi: 10.1038/s41598-019-49984-3. PMID:31537874 doi:http://dx.doi.org/10.1038/s41598-019-49984-3
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