Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases
Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases
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DOI：
10.1016/j.str.2009.06.002
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发表时间：
2009-07-15
期刊：
影响因子：
5.7
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Chowdhury, Rasheduzzaman;McDonough, Michael A.;Schofield, Christopher J.
缺氧诱导转录因子α亚基中脯氨酸残基的氧依赖性羟基化是动物缺氧反应的核心。HIF α的脯氨酰羟基化增加了其与von Hippel-Lindau蛋白（pVHL）的结合，因此通过泛素-蛋白酶体系统发出降解信号。HIF脯氨酰羟化酶（PHDs，脯氨酰羟化酶结构域酶）与胶原蛋白脯氨酰羟化酶相关，但与其Fe（II）辅因子和2-酮戊二酸辅底物形成异常稳定的复合物。我们报告了PHD 2（人类PHD中最重要的）催化结构域的晶体结构，该结构域与HIF-1 α的C末端氧依赖性降解结构域复合。连同生化分析，结果表明，PHD催化涉及一个移动的区域，隔离的羟基化位点和稳定的PHD2.Fe（II）.20 G复合物。这些结果将用于设计旨在治疗贫血和缺血性疾病的PHD抑制剂。
The oxygen-dependent hydroxylation of proline residues in the a subunit of hypoxia-inducible transcription factor (HIF alpha) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFa increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1 alpha. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).20G complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.