Abstract
The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic tem-per-ature or room tem-per-ature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple tem-per-atures from cryogenic to physiological, and another at high humidity. We inter-rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for Mpro, including a mobile zinc ion inter-leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra-molecular network bridging the active site and dimer inter-face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.
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