Optimization of a cyclic peptide inhibitor of Ser/Thr phosphatase PPM1D (Wip1).
Optimization of a cyclic peptide inhibitor of Ser/Thr phosphatase PPM1D (Wip1).
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DOI：
10.1021/bi101949t
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发表时间：
2011-05-31
期刊：
影响因子：
2.9
通讯作者：
Appella E
中科院分区：
文献类型：
--
作者：
Hayashi R;Tanoue K;Durell SR;Chatterjee DK;Jenkins LM;Appella DH;Appella E
PPM1D （PP2Cδ或Wip1）是一种野生型p53诱导的丝氨酸/苏氨酸磷酸酶，在DNA损伤后积累，属于PP2C家族。它使一些对细胞应激反应至关重要的蛋白去磷酸化和失活，包括p38 MAPK、p53和ATM。此外，PPM1D在许多人类癌症中被扩增和/或过表达。因此，抑制其活性可能构成一种重要的治疗干预新策略，以阻止几种不同癌症的进展。之前，我们报道了一种对PPM1D具有低微摩尔抑制活性的环硫醚肽的开发。在这里，我们描述了这类环肽抑制活性的重要改进，并根据结果提出了一个结合模型。我们发现，芳香环在X1位置与X5和X6位置的负电荷的特异性相互作用显著提高了环肽的抑制活性，优化后的分子Ki = 110 nM。据我们所知，这代表了PPM1D抑制剂报道的最高抑制活性。我们进一步开发了一种Ki = 2.9 μM的PPM1D优于PPM1A的抑制剂。环肽优化和诱变实验表明，PPM1D特有的高度碱性环与底物特异性有关。我们提出了PPM1D的催化位点和环肽抑制的新模型，这将有助于PPM1D抑制剂的后续设计和新底物的鉴定。
PPM1D (PP2Cδ or Wip1) was identified as a wild type p53-induced Ser/Thr phosphatase that accumulates after DNA damage and classified into the PP2C family. It dephosphorylates and inactivates several proteins critical for cellular stress responses, including p38 MAPK, p53, and ATM. Furthermore, PPM1D is amplified and/or overexpressed in a number of human cancers. Thus, inhibition of its activity could constitute an important new strategy for therapeutic intervention to halt the progression of several different cancers. Previously, we reported the development of a cyclic thioether peptide with low micromolar inhibitory activity towards PPM1D. Here, we describe important improvements in the inhibitory activity of this class of cyclic peptides and also present a binding model based upon the results. We found that specific interaction of an aromatic ring at the X1 position and negative charge at the X5 and X6 positions significantly increased the inhibitory activity of the cyclic peptide, with the optimized molecule having Ki = 110 nM. To the best of our knowledge, this represents the highest inhibitory activity reported for an inhibitor of PPM1D. We further developed an inhibitor selective for PPM1D over PPM1A with Ki = 2.9 μM. Optimization of the cyclic peptide and mutagenesis experiments suggest that a highly basic loop unique to PPM1D is related to substrate specificity. We propose a new model for the catalytic site of PPM1D and inhibition by the cyclic peptides that will be useful both for the subsequent design of PPM1D inhibitors and for identification of new substrates.
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影响因子：
3.4
作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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