Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones
Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones
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死亡相关蛋白激酶 1 与蒽醌相互作用的结构和热力学分析
DOI：
10.1107/s2059798320003940
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Mizuguchi Mineyuki
中科院分区：
文献类型：
--
作者：
Yokoyama Takeshi;Wijaya Peter;Kosaka Yuto;Mizuguchi Mineyuki
死亡相关蛋白激酶1(DAPK1)是一种丝氨酸/苏氨酸蛋白激酶，调节细胞凋亡和自噬。DAPK1被认为是治疗淀粉样蛋白β沉积、子宫内膜腺癌和急性缺血性中风的靶点。在这里，显示了对DAPK1磷酸化的有效抑制活性的天然蒽醌紫素。热力学分析表明，虽然紫红素的结合亲和力与含咪唑并氮的DAPK1抑制剂CPR005231相似，但紫红素的结合热效应更有利。此外，抑制势与结合热变有关，而与结合亲和力无关。对DAPK1-紫蛋白复合体的结晶学分析表明，氢键网络的形成可能有助于有利的焓变化，而富含甘氨酸的环的稳定可能导致不太有利的熵变化。本研究结果表明，紫红素可能是发现DAPK1抑制剂的良好先导化合物，观察其热效应变化可为药物开发提供重要线索。
Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase that regulates apoptosis and autophagy. DAPK1 is considered to be a therapeutic target for amyloid-β deposition, endometrial adenocarcinomas and acute ischemic stroke. Here, the potent inhibitory activity of the natural anthraquinone purpurin against DAPK1 phosphorylation is shown. Thermodynamic analysis revealed that while the binding affinity of purpurin is similar to that of CPR005231, which is a DAPK1 inhibitor with an imidazopyridazine moiety, the binding of purpurin was more enthalpically favorable. In addition, the inhibition potencies were correlated with the enthalpic changes but not with the binding affinities. Crystallographic analysis of the DAPK1–purpurin complex revealed that the formation of a hydrogen-bond network is likely to contribute to the favorable enthalpic changes and that stabilization of the glycine-rich loop may cause less favorable entropic changes. The present findings indicate that purpurin may be a good lead compound for the discovery of inhibitors of DAPK1, and the observation of enthalpic changes could provide important clues for drug development.