STRUCTURE OF HUMAN DNA REPAIR PROTEIN AGT

O-6-烷基鸟嘌呤-DNA烷基转移酶(AGT)是一种DNA修复酶 纠正DNA中致突变的O-6-甲基鸟嘌呤损伤的蛋白质 通过从鸟粪基团上除去烷基。在这个反应中， 烷基转移到活性基团的半胱氨酸残基 AGT的位置，使其失活。AGT活性升高是原因之一 针对肿瘤细胞对涉及DNA的癌症化疗的耐药性 烷基化反应，如氯乙基亚硝脲(Cenus)。因此， AGT的失活有效加强了当前的烷基化反应 化疗。一种AGT抑制剂，o-6-苄基鸟嘌呤，目前在 第二阶段的研究是这样一种强化疗法。开始一项计划 使用抑制剂AGT的基于结构的药物设计 O-6-苯基鸟嘌呤(BG)和O-6-(3-碘苯基)鸟嘌呤(IBG) 合成的。AGT与BG和IBG共结晶。绕射 来自AGT-BG复合体的数据在同步加速器上收集到2.3E 消息来源。目前，该复合体的重金属衍生品正在 被追捕。AGT-BG复合体的结构将用于 通过互补改进现有的缓蚀剂并产生新的缓蚀剂 到活动站点。

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.