PGLD FRAGMENT BASED SCREENING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 PglD是空肠弯曲杆菌N-连接糖蛋白生物合成途径中的一个重要酶。空肠弯曲菌是人类胃肠炎的主要原因，也是周围神经病格林-巴利综合征之前最常见的感染。已知在缺乏pglD的突变细菌中，空肠弯曲菌特异的蛋白质糖基化被破坏，并且这些细菌感染宿主的能力受到损害。在我们的实验室里，我们启动了一个项目，通过基于片段的筛选来开发一种有效的PglD抑制剂。我们鉴定了11个小分子(Mw&lt；300Da，S片段？)它们与PglD结合，我们试图通过X射线结晶学确定它们的结合方式。基本的结构信息将指导开发更紧密的PglD粘结剂，这些粘结剂将在我们的实验室合成和评估。预计这种方法将产生一种特定的、纳米分子的PglD抑制剂。有了这样的工具，我们将能够在体内控制N-糖基化，从而解开它的生物学作用。这种化合物也将具有治疗价值。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PglD is an essential enzyme in the N-linked glycoprotein biosynthetic pathway in the pathogenic bacteria Campylobacter jejuni. C. jejuni is the primary cause of gastroenteritis in humans and is the most frequent infection to precede the peripheral neuropathy Guillain-Barr¿¿ syndrome. It is known that the C. jejuni-specific protein glycosylation is disrupted in mutant bacteria lacking pglD, and that these bacteria are compromised in their ability to infect the host organism. In our lab we have initiated a project to develop an effective inhibitor of PglD by fragment-based screening. We have identified eleven small molecules (MW < 300 Da, ¿¿Sfragments¿¿?) which bind to PglD, and we seek to determine their binding mode by X-ray crystallography. The essential structural information will guide the development of tighter PglD binders which will be synthesized and evaluated in our laboratory. It is anticipated that this approach will result in a specific, nanomolar inhibitor of PglD. Armed with such a tool, we will be able to control N-glycosylation in vivo, thereby unraveling its biological roles. Such a compound will also be of therapeutic value.