STRUCTURE OF HUMAN DNA REPAIR PROTEIN AGT

人类 DNA 修复蛋白 AGT 的结构

• 批准号: 6119513
• 负责人: DOUGLAS S DANIELS
• 金额: --
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119513
• 关键词: biomaterials; enzymes; structural biology

O-6-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein which corrects promutagenic O-6-methylguanine lesions in DNA by removing the alkyl group from the guanyl moiety. In this reaction, the alkyl group is transferred to a cysteine residue in the active site of AGT, inactivating it. Elevated activity of AGT is responsible for resistance of tumor cells to cancer chemotherapies involving DNA alkylation such as chloroethylnitrosoureas (CENUs). Therefore, inactivation of AGT effectively potentiates current alkylation chemotherapies. One AGT inhibitor, o-6-benzylguanine, is currently in phase II studies as such a potentiation therapy. To begin a program of structure-based drug design using AGT, the inhibitors O-6-benyzlguanine (BG) and O-6-(3-iodobenzyl)guanine (IBG) were synthesized. AGT was cocrystallized with BG and IBG. Diffraction data from the AGT-BG complex was collected to 2.3 E at a synchotron source. Currently, heavy metal derivatives of the complex are being pursued. The structure of the AGT-BG complex will then be used to improve existing inhibitors and generate novel ones by complementation to the active site.

O-6-烷基鸟嘌呤-DNA 烷基转移酶 (AGT) 是一种 DNA 修复酶 纠正 DNA 中促突变​​ O-6-甲基鸟嘌呤损伤的蛋白质 通过从脒基部分除去烷基。 在这个反应中， 烷基被转移到活性物质中的半胱氨酸残基上 AGT 位点，使其失活。 AGT 活性升高是造成这种情况的原因 肿瘤细胞对涉及 DNA 的癌症化疗的耐药性 烷基化，例如氯乙基亚硝基脲（CENU）。 所以， AGT 失活可有效增强当前的烷基化作用 化疗。 一种 AGT 抑制剂邻-6-苄基鸟嘌呤目前正在研究中 II 期研究作为这种增强疗法。 开始一个程序 使用 AGT（抑制剂）进行基于结构的药物设计 O-6-苄基鸟嘌呤 (BG) 和 O-6-(3-碘苄基)鸟嘌呤 (IBG) 合成的。 AGT 与 BG 和 IBG 共结晶。 衍射 来自 AGT-BG 复合体的数据在同步加速器处收集至 2.3 E 来源。 目前，该配合物的重金属衍生物正在研究中。 追击。 AGT-BG 复合物的结构随后将用于 改进现有的抑制剂并通过互补产生新的抑制剂 到活动站点。