Unique, yet Typical Oxyanion Holes in Aspartic Proteases,ACS Catalysis

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Unique, yet Typical Oxyanion Holes in Aspartic Proteases
ACS Catalysis ( IF 11.3 ) Pub Date : 2020-11-20 , DOI: 10.1021/acscatal.0c03624
Mark Aldren M. Feliciano ₁ , Brian Gold ₁

Affiliation

From studies on pepsin nearly 200 years ago to the modern pursuit of drugs targeting renin, HIV protease, and β-secretases, aspartic proteases continue to shape the understanding of proteins. Though their structure and reactivity are of great interest for the design of therapeutics, mechanistic details remain elusive. We reveal within a stereoelectronic link between “the most obscure of all the proteases” and the oxyanion hole of serine proteases—the vivid illustration of nature’s catalytic strategy of transition state stabilization. Specifically, rate-limiting breakdown of the tetrahedral intermediate is facilitated by n → π* donation from the forming C-terminus into an active-site glycine. Cooperative H-bonds strengthen this rare, if not unreported, mode of enzyme catalysis in a fashion resembling that found in serine proteases. Exploiting this interaction provides a strategy for the design of next-generation inhibitors.

中文翻译：

天冬氨酸蛋白酶中独特但典型的Oxyanion孔

从将近200年前对胃蛋白酶的研究到对肾素，HIV蛋白酶和β-分泌酶的药物的现代追求，天冬氨酸蛋白酶继续影响人们对蛋白质的理解。尽管它们的结构和反应性对于治疗剂的设计非常感兴趣，但是机械细节仍然难以捉摸。我们在“所有蛋白酶中最晦涩的”与丝氨酸蛋白酶的氧阴离子孔之间的立体电子联系中揭示了这一点，这是自然界过渡态稳定催化策略的生动例证。具体而言，通过形成C的n→π*的贡献促进了四面体中间体的限速分解-末端变成活性位点甘氨酸。协作的氢键以类似于丝氨酸蛋白酶的方式增强了这种罕见的（即使未报告的）酶催化模式。利用这种相互作用为设计下一代抑制剂提供了一种策略。

更新日期：2020-12-04

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