Targeting Protein-Protein Interactions in the HIF System.
Targeting Protein-Protein Interactions in the HIF System.
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DOI：
10.1002/cmdc.201600012
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发表时间：
2016-04-19
期刊：
影响因子：
3.4
通讯作者：
Schofield CJ
中科院分区：
文献类型：
--
作者：
Wilkins SE;Abboud MI;Hancock RL;Schofield CJ
动物通过增加称为缺氧诱导因子（HIF）的转录因子的水平来对慢性缺氧做出反应。HIF上调多个基因，其产物在细胞和全身水平上改善有限氧气的影响。HIF系统的缺氧感知涉及HIF α亚基的羟化酶催化的翻译后修饰，其1）发出HIF-α降解的信号，2）限制HIF与转录辅激活蛋白的结合。 由于缺氧反应与多种疾病状态相关，因此HIF介导的反应的治疗操作具有相当大的医学潜力。除了调节HIF羟化酶的催化作用外，HIF系统还表现出涉及蛋白质-蛋白质和蛋白质-核酸相互作用的治疗干预的其他可能性。我们对HIF系统的结构生物学和生物化学的理解的最新进展正在促进药物化学的努力。在这里，我们给出了一个概述的缺氧诱导因子系统，专注于蛋白质-蛋白质相互作用的结构知识，以及如何这可能是用来调节缺氧反应的治疗效益。
Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia‐inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase‐catalysed post‐translational modifications of the HIF α‐subunits, which 1) signal for degradation of HIF‐α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF‐mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein–protein and protein–nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein–protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.