PDF(Pubmed)
Abstract：
Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
摘要：
人异柠檬酸脱氢酶1（IDH1）的突变通过用产生代谢产物的新形态活性代替其常规活性来驱动多种癌症中的肿瘤形成。对肿瘤驱动IDH1突变体之间的机制差异了解甚少。我们先前报道，R132Q突变体独特地保留了常规活性，同时催化了强大的代谢产物产生，允许在单个活性位点内比较这些反应机制的机会。这里,我们采用静态和动态结构方法，发现，与R132H相比，R132Q活性位点采用了为催化引发的构象，具有优化的底物结合和氢化物转移，以驱动R132H上改善的常规和新形态活性。这种活性位点重塑揭示了对选择性突变IDH1治疗性抑制剂的抗性的可能机制。这项工作增强了我们对基本IDH1机制的理解，同时精确定位了改善抑制剂选择性的区域。
