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