The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase
Yousef M. Alhammad, M.M. Kashipathy, Anuradha Roy, Jean‐Philippe Gagné, Peter R. McDonald, Philip Gao, Louis Nonfoux, K.P. Battaile, David K. Johnson, Erik D. Holmstrom, Guy G. Poirier, Scott Lovell, Anthony R. Fehr
Abstract
SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused more than 1.2 million deaths worldwide. With no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic posttranslational process that is increasingly being recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose and describe its ADP-ribose binding and hydrolysis activities in direct comparison to those of SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.