PGLD FRAGMENT BASED SCREENING

基于 PGLD 片段的筛选

• 批准号: 8363335
• 负责人: JAMES A MORRISON
• 金额: $ 0.57万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363335
• 关键词: Bacteria; Binding; Biological; Campylobacter jejuni; Crystallography; Development; Enzymes; Funding; Gastroenteritis; Glycoproteins; Grant; Guillain-Barré Syndrome; Human; Infection; Laboratories; Light; Link; National Center for Research Resources; Organism; Pathway interactions; Peripheral Nervous System Diseases; Principal Investigator; Protein Glycosylation; Research; Research Infrastructure; Resources; Role; Screening procedure; Source; Synchrotrons; Therapeutic; United States National Institutes of Health; X-Ray Crystallography; arm; base; cost; glycosylation; in vivo; inhibitor/antagonist; mutant; pathogenic bacteria; small molecule; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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, "fragments") 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 PglD是病原菌空肠弯曲菌中N-连接糖蛋白生物合成途径中的必需酶。C.空肠是人类胃肠炎的主要原因，并且是周围神经病变格林-巴利综合征之前最常见的感染。已知C.在缺乏pglD的突变细菌中，空肠特异性蛋白糖基化被破坏，并且这些细菌感染宿主生物体的能力受到损害。在我们的实验室中，我们已经启动了一个项目，通过基于片段的筛选来开发PglD的有效抑制剂。 我们已经鉴定了11个与PglD结合的小分子（MW < 300 Da，“片段”），并且我们试图通过X射线晶体学确定它们的结合模式。基本的结构信息将指导开发更紧密的PglD粘合剂，该粘合剂将在我们的实验室中合成和评估。预期该方法将产生PglD的特异性纳摩尔抑制剂。有了这样的工具，我们将能够在体内控制N-糖基化，从而揭示其生物学作用。这样的化合物也将具有治疗价值。