Structural Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524 Binding in SARS-CoV-2 Macrodomain

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP- ribosylation sites during SARS-CoV-2 infection. Thus targeting this protein domain may offer a therapeutic strategy to combat current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally occurring nucleotides, small molecules, and nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and provide chemical starting points for future inhibitor development.

Automated summary

The nsP3 macrodomain is crucial in regulating the host immune response during SARS-CoV-2 infection by recognizing and removing posttranslational ADP-ribosylation sites. Targeting this protein domain could provide a therapeutic strategy for combating virus pandemics. Crystal structures complexed with diverse nucleotides, small molecules, and nucleotide analogues, including active metabolites of remdesivir, provide valuable insights for inhibitor development.