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

Authors

Ali Ebrahim, CUNY Advanced Science Research Center
Blake T. Riley, CUNY Advanced Science Research CenterFollow
Desigan Kumaran, Brookhaven National Laboratory
Babak Andi, Brookhaven National Laboratory
Martin R. Fuchs, Brookhaven National Laboratory
Sean McSweeney, Brookhaven National Laboratory
Daniel A. Keedy, CUNY City CollegeFollow

Document Type

Working Paper

Publication Date

11-7-2021

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.

Comments

This pre-print was originally posted on bioRxiv, available at https://doi.org/10.1101/2021.05.03.437411.

The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.