Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14,ACS Chemical Biology

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Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-10-19 00:00:00 , DOI: 10.1021/acschembio.7b00445
Marion Schuller _{1,

2} , Kerstin Riedel ₃ , Ian Gibbs-Seymour ₄ , Kristin Uth ₁ , Christian Sieg ₁ , André P. Gehring ₃ , Ivan Ahel ₄ , Franz Bracher ₃ , Benedikt M. Kessler ₂ , Jonathan M. Elkins ₁ , Stefan Knapp _{1,

5,

6}

Affiliation

Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localization to sites of DNA damage.

中文翻译：

发现选择性变构抑制剂靶向大域2的腺苷二磷酸核糖聚合酶14。

宏域是保守的蛋白质相互作用模块，可以在生命的所有域（包括某些病毒）中找到。大域介导具有二磷酸腺苷核糖（ADPR）修饰的序列基序的识别，从而调节多种细胞过程。由于其在癌症或病毒发病机理中的作用，大域已成为潜在的治疗靶标，但迄今为止，小分子抑制剂的缺乏已阻碍了靶标验证研究。在这里，我们描述了一种有效的筛选策略，用于识别从大域置换ADPR的小分子抑制剂。我们报告发现和表征的大域抑制剂，GeA-69，选择性靶向具有低微摩尔亲和力的PARP14的大域2（MD2）。GeA-69类似物与PARP14 MD2的共结晶揭示了变构结合机制，这解释了其对其他人大域的选择性。我们表明，GeA-69参与完整细胞中的PARP14 MD2并防止其定位到DNA损伤的位点。

更新日期：2017-10-19

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