A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity
A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity
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DOI：
10.1016/j.chembiol.2018.09.011
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发表时间：
2018-12-01
影响因子：
8.6
通讯作者：
Cohen, Michael S.
中科院分区：
文献类型：
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作者：
Kirby, Ilsa T.;Kojic, Ana;Cohen, Michael S.
聚腺苷二磷酸核糖聚合酶（PARP 1 -16）在多种细胞过程中起着关键作用。催化聚ADP核糖基化（PAR化）的PARP是最好表征的PARP家族成员，因为这些PARP的有效和选择性抑制剂是可用的。在开发催化单ADP核糖基化（MARylation）的PARP的选择性小分子抑制剂方面取得的成功相对较少，限制了我们对MARylation细胞作用的理解。在这里，我们描述了结构导向的设计抑制剂的PARP催化MARylation。最具选择性的类似物ITK 7有效抑制PARP 11的MARylation活性，PARP 11是一种核定位的PARP。ITK 7的选择性超过其他PARP家族成员200倍。使用活细胞成像，我们表明ITK 7导致PARP 11从核膜中解离。这些结果表明PARP 11的细胞定位受其催化活性调节。
Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.