School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Eur J Med Chem. 2017 Oct 20;139:482-491. doi: 10.1016/j.ejmech.2017.08.024. Epub 2017 Aug 10.
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.
牙龈卟啉单胞菌是一种革兰氏阴性厌氧菌，与慢性牙周炎有关。具有高二肽基肽酶 4 (DPP4) 表达能力的牙龈卟啉单胞菌临床分离株也具有较强的生物膜形成能力和感染力。牙龈卟啉单胞菌 DPP4 的 X 射线晶体结构在 2.2 Å 分辨率下得到解决。尽管序列同一性为 32%，但二聚体的整体结构在牙龈卟啉单胞菌 DPP4 和哺乳动物同源物之间是保守的。除了称为 S2-广泛的区域外，底物结合位点的结构也保持保守，该区域被目前用作抗糖尿病药物的特定人类 DPP4 抑制剂所利用。对 450 种化合物的筛选作为抑制剂显示出部分模仿哺乳动物 DPP9 的结构-活性关系。使用 124 种潜在的肽底物证实了人类和细菌 DPP4 之间的功能相似性。
