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位点相互作用，包括 胃蛋白酶、组织蛋白酶D和肾素。 这项工作对一个全面的 了解这些酶的作用机制，并设计 用于控制高血压的特异性肾素抑制剂。 的方法 本研究主要涉及胃蛋白酶抑制剂和胃蛋白酶抑制剂的1H和13C NMR研究 与猪胃蛋白酶结合的类似物。 具体而言，氘代类似物将是 以及13C标记的胃酶抑制素衍生物。 目标是 提供了强相互作用的详细分子描述 在酸性蛋白酶的活性部位具有氨基酸基团的抑制剂。 大部分研究将致力于利用这一发现 胃蛋白酶抑制剂的酮类似物，与底物等排，并富集 与羰基中的13 C，提供直接的13 C NMR证据，形成 四面体中间体结合胃蛋白酶。 研究还将 通过1H NMR对在上发现的寡糖的溶液构象进行测定。 一些乙酰基蛋白酶。

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.