Ruf A, de Murcia G, Schulz G E
Institut für Organische Chemie und Biochemie, Freiburg im Breisgau, Germany.
Biochemistry. 1998 Mar 17;37(11):3893-900. doi: 10.1021/bi972383s.
Inhibitors of poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) are of clinical interest because they have potential for improving radiation therapy and chemotherapy of cancer. The refined binding structures of four such inhibitors are reported together with the refined structure of the unligated catalytic fragment of the enzyme. Following their design, all inhibitors bind at the position of the nicotinamide moiety of the substrate NAD+. The observed binding mode suggests inhibitor improvements that avoid other NAD(+)-binding enzymes. Because the binding pocket of NAD+ has been strongly conserved during evolution, the homology with ADP-ribosylating bacterial toxins could be used to extend the bound nicotinamide, which is marked by the inhibitors, to the full NAD+ molecule.
聚（ADP - 核糖）聚合酶（PARP，EC 2.4.2.30）抑制剂具有临床意义，因为它们具有改善癌症放射治疗和化疗的潜力。本文报道了四种此类抑制剂的精确结合结构以及该酶未结合配体的催化片段的精确结构。在设计之后，所有抑制剂都结合在底物NAD + 的烟酰胺部分的位置。观察到的结合模式提示了抑制剂的改进方向，即避免与其他NAD(+)结合酶相互作用。由于NAD + 的结合口袋在进化过程中得到了强烈的保守，与ADP - 核糖基化细菌毒素的同源性可用于将抑制剂标记的结合烟酰胺扩展到完整的NAD + 分子。
