Oliver Antony W, Amé Jean-Christophe, Roe S Mark, Good Valerie, de Murcia Gilbert, Pearl Laurence H
Cancer Research UK DNA Repair Enzyme Group, Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Nucleic Acids Res. 2004 Jan 22;32(2):456-64. doi: 10.1093/nar/gkh215. Print 2004.
Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors.
聚（ADP - 核糖）聚合酶 -1（PARP -1）已成为癌症治疗中的一个重要药理学靶点，因为它在细胞中作为“DNA链断裂传感器”发挥作用，这在一定程度上导致对某些现有化疗和放疗产生抗性。目前已开发出抑制剂，可阻止PARP -1响应DNA断裂而合成聚（ADP - 核糖），并增强DNA损伤剂的细胞毒性。然而，随着最近发现具有类似DNA损伤依赖性催化活性的PARP -2以及其他含有“PARP催化”特征的成员，现有抑制剂的同工型选择性和由此产生的药理作用受到质疑。我们在此展示了小鼠PARP -2催化片段的晶体结构，分辨率为2.8埃，并将其与PARP -1的催化片段进行比较，重点是提供一个合理药物设计的可能框架，以便开发未来的同工型特异性抑制剂。
