Structural basis for ligand promiscuity in cytochrome P450 3A4
Structural basis for ligand promiscuity in cytochrome P450 3A4
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DOI：
10.1073/pnas.0603236103
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发表时间：
2006-09-12
影响因子：
11.1
通讯作者：
Sjogren, Tove
中科院分区：
文献类型：
--
作者：
Ekroos, Marika;Sjogren, Tove
细胞色素P450 (CYP) 3A4是人类CYP酶中最混杂的一种，对大约50%的上市药物的代谢有贡献。它也是最常参与不必要的药物-药物相互作用的同种异构体。因此，更好地了解控制cyp3a4 -配体相互作用的分子机制对任何药物发现工作都非常重要。在这里，我们展示了人CYF ' 3A4与两种已被很好表征的药物：酮康唑和红霉素配合物的晶体结构。与先前的报道相反，该蛋白在配体结合后发生了巨大的构象变化，活性位点体积增加了80%。由于酮康唑和红霉素诱导不同类型的坐标移位，这些结构代表了CYF3A4的两种不同的开放构象。酮康唑两分子与CYP3A4活性位点的结合以及红霉素多种结合模式的明确指示，对CYP3A4经常显示的非典型动力学数据的解释具有重要意义。在没有相关实验数据支持的情况下，当前结构所显示的极端灵活性也挑战了任何应用计算设计工具的尝试。
Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of approximate to 50% of marketed drugs. It is also the isoform most often involved in unwanted drug-drug interactions. A better understanding of the molecular mechanisms governing CYP3A4-ligand interaction therefore would be of great importance to any drug discovery effort. Here, we present crystal structures of human CYF`3A4 in complex with two well characterized drugs: ketoconazole and erythromycin. in contrast to previous reports, the protein undergoes dramatic conformational changes upon ligand binding with an increase in the active site volume by > 80%. The structures represent two distinct open conformations of CYF3A4 because ketoconazole and erythromycin induce different types of coordinate shifts. The binding of two molecules of ketoconazole to the CYP3A4 active site and the clear indication of multiple binding modes for erythromycin has implications for the interpretation of the atypical kinetic data often displayed by CYP3A4. The extreme flexibility revealed by the present structures also challenges any attempt to apply computational design tools without the support of relevant experimental data.