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首页> 外文期刊>The FEBS journal >Crystal structures of human 17 beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP(+) reveal the mechanism of substrate inhibition
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Crystal structures of human 17 beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NADP(+) reveal the mechanism of substrate inhibition

机译：用雌激素和NADP（+）络合的人17β-羟类脱氢酶1型晶体结构揭示了基材抑制的机理

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Human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) catalyses the last step in estrogen activation and is thus involved in estrogen-dependent diseases (EDDs). Unlike other 17 beta-HSD members, 17 beta-HSD1 undergoes a significant substrate-induced inhibition that we have previously reported. Here we solved the binary and ternary crystal structures of 17 beta-HSD1 in complex with estrone (E1) and cofactor analog NADP(+), demonstrating critical enzyme-substrate-cofactor interactions. These complexes revealed a reversely bound E1 in 17 beta-HSD1 that provides the basis of the substrate inhibition, never demonstrated in estradiol complexes. Structural analysis showed that His(221) is the key residue responsible for the reorganization and stabilization of the reversely bound E1, leading to the formation of a dead-end complex, which exists widely in NADP(H)-preferred enzymes for the regulation of their enzymatic activity. Further, a new inhibitor is proposed that may inhibit 17 beta-HSD1 through the formation of a dead-end complex. This finding indicates a simple mechanism of enzyme regulation in the physiological background and introduces a pioneer inhibitor of 17 beta-HSD1 based on the dead-end inhibition model for efficiently targeting EDDs. Databases Coordinates and structure factors of 17 beta-HSD1-E1 and 17 beta-HSD1-E1-NADP(+) have been deposited in the Protein Data Bank with accession code and respectively. Enzymes 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) EC 1.1.1.62.
机译：人17β-羟类脱氢酶1（17β-HSD1）催化雌激素活化的最后一步，因此参与雌激素依赖性疾病（EDDS）。与其他17个β-HSD成员不同，17β-HSD1经历了我们先前报道的显着基质诱导的抑制。在这里，我们用雌激素（E1）和Cofactor模拟NADP（+）解决了17β-HSD1的二元和三元晶体结构，证明了关键酶 - 基质 - 辅因子相互作用。这些配合物在17β-HSD1中揭示了逆合的E1，其提供基础抑制的基础，从未在雌二醇配合物中证明。结构分析表明，他（221）是负责重新结合E1的重组和稳定的关键残留物，导致死终复合物的形成，其中存在于NADP（H）的酶的调节中存在他们的酶活性。此外，提出了一种新的抑制剂，其可以通过形成死端络合物来抑制17β-HSD1。该发现表明了生理背景中的酶调节的简单机制，并基于死端抑制模型引入17β-HSD1的先驱抑制剂，以有效地靶向EDD。数据库坐标和17β-HSD1-E1和17 Beta-HSD1-E1-NADP（+）的结构因子已被沉积在蛋白质数据库中，分别为加入守则。酶17β-羟类脱氢酶1（17β-HSD1）EC 1.1.1.62。

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