ACID PROTEASE STRUCTURE, DYNAMICS AND MECHANISM

这项研究的目的是详细了解抑制剂(和 底物)与酸性蛋白酶的活性部位相互作用，包括 胃酶、天冬氨酸D和肾素。这项工作对整个社会都很重要 了解这些酶的作用机制，并用于设计 用于控制高血压的肾素特异性抑制剂。其方法是 研究主要涉及胃抑素和胃抑素的~1H和~(13)C核磁共振研究 与猪胃酶结合的类似物。具体来说，氢化类似物将是 以及13C标记的胃抑素衍生物。我们的目标是 提供了强相互作用的详细分子描述 酸性蛋白水解酶活性部位含有氨基酸基团的抑制剂。 许多研究将被引导到利用这一发现的方向 即酮类似于胃抑素，与底物异构化，并浓缩 在羰基上有13C，为形成的直接13C核磁共振证据 与胃酶结合时的四面体中间体。研究也将是 用~1H核磁共振研究低聚糖的溶液构象 一些天冬氨酸蛋白酶。

The aim of this research is to understand in detail how inhibitors (and substrates) interact with the active sites of acid proteases, including pepsin, cathespin D and renin. The work has importance for a full understanding of the mechanism of action of these enzymes, and for design of specific inhibitors of renin for control of hypertension. The method of study involves mainly 1H and 13C NMR studies of pepstatin and pepstatin analogs binding to porcine pepsin. Specifically deuterated analogs will be used, as well as 13C labeled pepstatin derivatives. The objective is to provide a detailed molecular description of the interaction of strong inhibitors with amino acid groups in the active site of acid proteases. Much of the research will be directed to take advantage of the discovery that ketone analogs of pepstatin, isosteric with substrates, and enriched with 13C in the carbonyl, provide direct 13C NMR evidence for formation of tetrahedral intermediates upon binding to pepsin. Studies will also be done by 1H NMR on the solution conformation of oligosaccharides found on some aspartyl protease enzymes.