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The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M ^pro ).

ABSTRACT: The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M ^pro , is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M ^pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M ^pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M ^pro , including mobile solvent interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19 and combat future coronavirus pandemics.

Synopsis

X-ray crystallography at variable temperature for SARS-CoV-2 M ^pro reveals a complex conformational landscape, including mobile solvent at the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and an intramolecular network bridging the active site and dimer interface.

SUBMITTER: Ebrahim A

PROVIDER: S-EPMC8109201 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).

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