Harnessing the Evolvability of Tricyclic Microviridins To Dissect Protease-Inhibitor Interactions
Harnessing the Evolvability of Tricyclic Microviridins To Dissect Protease-Inhibitor Interactions
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DOI：
10.1002/anie.201309721
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发表时间：
2014-04-01
影响因子：
16.6
通讯作者：
Dittmann, Elke
中科院分区：
文献类型：
--
作者：
Weiz, Annika R.;Ishida, Keishi;Dittmann, Elke
了解和控制蛋白质水解是治疗化学的一个重要目标。在特异性抑制蛋白酶的天然产物中，微病毒素是特别值得注意的。微病毒蛋白是核糖体产生的和后修饰的肽，其被加工成独特的笼状结构。在这里，我们报告了一个合理的和随机的诱变方法，提供了基本的见解选择性赋予部分的microviridins。有效的变体microviridin J与胰蛋白酶共结晶，并首次确定了microviridins的三维结构，并揭示了抑制模式。
Understanding and controlling proteolysis is an important goal in therapeutic chemistry. Among the natural products specifically inhibiting proteases microviridins are particularly noteworthy. Microviridins are ribosomally produced and posttranslationally modified peptides that are processed into a unique, cagelike architecture. Here, we report a combined rational and random mutagenesis approach that provides fundamental insights into selectivity-conferring moieties of microviridins. The potent variant microviridin J was co-crystallized with trypsin, and for the first time the three-dimensional structure of microviridins was determined and the mode of inhibition revealed.