Year: 2022
Type: article
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.
Source: IUCrJ
Language: English
Subfield: Materials Chemistry
Field: Materials Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,200
Awards: G1104325616, G1285306620, G1867732070, G1868695577, G2004402655, G241279073, G2962318713, G3067052642, G3262563802, G357145406, G3728080647, G3850097093, G4920325777, G4972998915, G5417557083, G5514976981, G5633341255, G5765906131, G6476969910, G6733788163, G7463374569, G8572393207, G8701900045, G9000045166, G9000344906, Center for Biomolecular Structure (CBMS)
OpenAlex ID: W4292065984