Porphyromonas gingivalis 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. P. gingivalis 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 149 , Glu 182 , Asp 183 , Asp 218 , Asp 267 and His 299 . In addition, we could observe that a non-conserved Trp 193 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.

中文翻译：

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牙龈卟啉单胞菌谷氨酰胺酰环化酶的结构和动力学表征

牙龈卟啉单胞菌是一种已知参与慢性牙周炎发病机制的细菌物种，最近它也与阿尔茨海默病有关。P. gingivalis 表达一种谷氨酰胺酰环化酶 (PgQC)，其人类直系同源物已知参与 β 淀粉样肽代谢。我们已经阐明了未结合和抑制剂复合形式的 PgQC 晶体结构，分辨率为 1.95 Å。PgQC 的结构表征证实 PgQC 显示哺乳动物折叠而不是细菌折叠。我们的生化表征表明，PgQC 使用由残基 Asp 149、Glu 182、Asp 183、Asp 218、Asp 267 和 His 299 启用的类似哺乳动物的催化机制。此外，我们可以观察到非保守的 Trp 193 可能会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，我们确定了一种苯并咪唑衍生物，可在低微摩尔范围内抑制 PgQC，这可能适用于进一步的药物化学开发。