Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu215123, China.
Department of Health and Environmental Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu215123, China.
Biol Chem. 2021 Apr 7;402(7):759-768. doi: 10.1515/hsz-2020-0298. Print 2021 Jun 25.
is a bacterial species known to be involved in the pathogenesis of chronic periodontitis, that more recently has been as well associated with Alzheimer's disease. expresses a glutaminyl cyclase (PgQC) whose human ortholog is known to participate in the beta amyloid peptide metabolism. We have elucidated the crystal structure of PgQC at 1.95 Å resolution in unbound and in inhibitor-complexed forms. The structural characterization of PgQC confirmed that PgQC displays a mammalian fold rather than a bacterial fold. Our biochemical characterization indicates that PgQC uses a mammalian-like catalytic mechanism enabled by the residues Asp, Glu, Asp, Asp, Asp and His. In addition, we could observe that a non-conserved Trp may drive differences in the binding affinity of ligands which might be useful for drug development. With a screening of a small molecule library, we have identified a benzimidazole derivative rendering PgQC inhibition in the low micromolar range that might be amenable for further medicinal chemistry development.
是一种已知与慢性牙周炎发病机制有关的细菌物种，最近也与阿尔茨海默病有关。它表达一种谷氨酰胺环化酶（PgQC），其人类同源物已知参与β淀粉样肽代谢。我们已经阐明了 PgQC 在未结合和抑制剂复合物形式下的 1.95Å 分辨率的晶体结构。PgQC 的结构特征证实，PgQC 显示出哺乳动物折叠而不是细菌折叠。我们的生化特征表明，PgQC 使用一种类似于哺乳动物的催化机制，由残基 Asp、Glu、Asp、Asp、Asp 和 His 启用。此外，我们可以观察到非保守的色氨酸可能导致配体结合亲和力的差异，这可能对药物开发有用。通过对小分子文库的筛选，我们已经鉴定出一种苯并咪唑衍生物，它在低微摩尔范围内抑制 PgQC，这可能适合进一步的药物化学开发。
