STRUCTURE OF HUMAN DNA REPAIR PROTEIN AGT

O-6-烷基鸟嘌呤-DNA烷基转移酶（O-6-Alkylguanine-DNA alkyltransferase，AGT）是一种DNA修复酶 一种纠正DNA中前诱变性O-6-甲基鸟嘌呤损伤的蛋白质 通过从鸟苷基部分除去烷基。 在这个反应中， 所述烷基转移至活性化合物中的半胱氨酸残基， AGT的活性升高， 肿瘤细胞对涉及DNA的癌症化疗的抗性 烷基化如氯乙基亚硝基脲（CENUs）。 因此，我们认为， AGT失活有效地增强了当前烷基化 化疗 一种AGT抑制剂，o-6-苄基鸟嘌呤，目前在 II期研究作为这样的增强疗法。 开始程序 基于结构的药物设计，使用AGT， O-6-苄基鸟嘌呤（BG）和O-6-（3-碘苄基）鸟嘌呤（IBG）分别为 合成了 AGT与BG和IBG共结晶。 衍射 来自AGT-BG复合物的数据在同步加速器上收集至2.3E 源头 目前，该络合物的重金属衍生物正在被 追求。 AGT-BG复合物的结构将用于 改进现有抑制剂并通过互补产生新的抑制剂 到活跃的网站。

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.