X-Ray Structure Determination of LpxC

LpxC 的 X 射线结构测定

• 批准号: 6663290
• 负责人: DOUGLAS A WHITTINGTON
• 金额: $ 2.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663290
• 关键词: Escherichia coli; X ray crystallography; acetylation; active sites; amidohydrolases; bacterial polysaccharides; bacterial proteins; binding sites; carbohydrate metabolism; computer simulation; crystallization; drug resistance; enzyme inhibitors; enzyme mechanism; enzyme model; enzyme reconstitution; enzyme substrate complex; intermolecular interaction; metalloenzyme; model design /development; protein folding; protein structure function; proteomics; site directed mutagenesis; structural biology; zinc

Bacteria are evolving immunity to the current generation of antibiotic drugs, raising the need for new drugs and new drug targets. This proposal presents a plan for the structural determination of one such target, the Zn-dependent UDP-3-O-(R-hydroxymyristoyl)-N- acetylglucosamine deacetylase (LpxC) from Aquifex aeolicus. LpxC catalyzes the first committed step in the synthesis of lipid A, the membrane anchor of the principle component of the outer membrane of E. coli and other Gram-negative bacteria. Inhibited lipid A production either kills bacteria or renders them permeable to antibiotics that are normally blocked from entry into the cell. An X-ray crystal structure of LpxC will allow identification of the key features involved in substrate binding and zinc ion coordination, which in turn will aid in the development of new therapeutics that may be bactericidal alone or in conjunction with other known antibiotics.

细菌正在发展对当前一代抗生素药物的免疫力，从而增加了对新药和新药物靶标的需求。该提案提出了一个计划确定一个这样一个靶标的Zn依赖性UDP-3-O-（R-羟基甲酰胺）-N-乙酰基葡萄糖胺脱乙酰基酶（LPXC）的计划。 LPXC催化了脂质A的合成，这是大肠杆菌外膜和其他革兰氏阴性细菌的原理成分的膜锚。抑制脂质的生产可杀死细菌，或者使其渗透到通常从进入细胞中被阻断的抗生素。 LPXC的X射线晶体结构将允许鉴定底物结合和锌离子协调所涉及的关键特征，这反过来又有助于开发新的疗法，这些疗法可能单独或与其他已知抗生素结合使用。