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首页> 外文期刊>Journal of the American Chemical Society >Selective Phosphorylation Inhibitor of Delta Protein Kinase C-Pyruvate Dehydrogenase Kinase Protein-Protein Interactions: Application for Myocardial Injury in Vivo
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Selective Phosphorylation Inhibitor of Delta Protein Kinase C-Pyruvate Dehydrogenase Kinase Protein-Protein Interactions: Application for Myocardial Injury in Vivo

机译：δ蛋白激酶C-丙酮酸脱氢酶激酶蛋白-蛋白质相互作用的选择性磷酸化抑制剂：在体内心肌损伤中的应用

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摘要

Protein kinases regulate numerous cellular processes, including cell growth, metabolism, and cell death. Because the primary sequence and the three-dimensional structure of many kinases are highly similar, the development of selective inhibitors for only one kinase is challenging. Furthermore, many protein kinases are pleiotropic, mediating diverse and sometimes even opposing functions by phosphorylating multiple protein substrates. Here, we set out to develop an inhibitor of a selective protein kinase phosphorylation of only one of its substrates. Focusing on the pleiotropic delta protein kinase C (δPKC), we used a rational approach to identify a distal docking site on δPKC for its substrate, pyruvate dehydrogenase kinase (PDK). We reasoned that an inhibitor of PDK's docking should selectively inhibit the phosphorylation of only PDK without affecting phosphorylation of the other δPKC substrates. Our approach identified a selective inhibitor of PDK docking to δPKC with an in vitro K_d of ～50 nM and reducing cardiac injury IC_(50) of ～5 nM. This inhibitor, which did not affect the phosphorylation of other δPKC substrates even at 1 μM, demonstrated that PDK phosphorylation alone is critical for δPKC- mediated injury by heart attack The approach we describe is likely applicable for the identification of other substrate-specific kinase inhibitors.
机译：蛋白激酶调节许多细胞过程，包括细胞生长，代谢和细胞死亡。由于许多激酶的一级序列和三维结构高度相似，因此开发仅一种激酶的选择性抑制剂具有挑战性。此外，许多蛋白激酶是多效的，通过磷酸化多种蛋白底物来介导多种功能，有时甚至是相反的功能。在这里，我们着手开发仅一种底物的选择性蛋白激酶磷酸化抑制剂。着眼于多效性δ蛋白激酶C（δPKC），我们使用了一种合理的方法来确定δPKC底物丙酮酸脱氢酶激酶（PDK）在远端的对接位点。我们认为，PDK对接的抑制剂应选择性地仅抑制PDK的磷酸化，而不会影响其他δPKC底物的磷酸化。我们的方法确定了PDK对接至δPKC的选择性抑制剂，其体外K_d为〜50 nM，减少心脏损伤的IC_（50）为〜5 nM。该抑制剂即使在1μM时也不会影响其他δPKC底物的磷酸化，证明单独的PDK磷酸化对于心脏病发作由δPKC介导的损伤至关重要。我们描述的方法可能适用于鉴定其他底物特异性激酶抑制剂。

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  • 来源
    《Journal of the American Chemical Society》 |2016年第24期|7626-7635|共10页
  • 作者

    Nir Qvit; Marie-Helene Disatnik; Eiketsu Sho; Daria Mochly-Rosen;

  • 作者单位

    Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, California 94305-5174, United States;

    Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, California 94305-5174, United States;

    Nanjing, Jiangsu 210000, P.R. China;

    Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, California 94305-5174, United States;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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