Congratulations to Professor Brian Gold for having an article published in the American Chemical Society!

Departmental News

Posted:  Nov 20, 2020 - 12:00am



Research Article: Unique, yet Typical Oxyanion Holes in Aspartic Proteases

Mark Aldren M. Feliciano and Brian Gold


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.

Abstract Image