Congratulations to Professor Brian Gold for having an article published in the American Chemical Society!
Posted: Nov 20, 2020 - 12:00am
Research Article: Unique, yet Typical Oxyanion Holes in Aspartic Proteases
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.