8DD6

SARS-CoV-2 Main Protease (Mpro) H163A Mutant in Complex with GC376

Summary for 8DD6

• Entry DOI: 10.2210/pdb8dd6/pdb
• Related PRD ID: PRD_002495
• Descriptor: ORF1a polyprotein, DIMETHYL SULFOXIDE, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (4 entities in total)
• Functional Keywords: cysteine protease, sars-cov-2, 3cl-like, gc376, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34322.16

Authors

Tran, N.,McLeod, M.J.,Kalyaanamoorthy, S.,Ganesan, A.,Holyoak, T. (deposition date: 2022-06-17, release date: 2023-09-27, Last modification date: 2024-10-30)

Primary citation

Tran, N.,Dasari, S.,Barwell, S.A.E.,McLeod, M.J.,Kalyaanamoorthy, S.,Holyoak, T.,Ganesan, A.
The H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease.
Nat Commun, 14:5625-5625, 2023

PubMed Abstract: The main protease of SARS-CoV-2 (Mpro) is an important target for developing COVID-19 therapeutics. Recent work has highlighted Mpro's susceptibility to undergo redox-associated conformational changes in response to cellular and immune-system-induced oxidation. Despite structural evidence indicating large-scale rearrangements upon oxidation, the mechanisms of conformational change and its functional consequences are poorly understood. Here, we present the crystal structure of an Mpro point mutant (H163A) that shows an oxidized conformation with the catalytic cysteine in a disulfide bond. We hypothesize that Mpro adopts this conformation under oxidative stress to protect against over-oxidation. Our metadynamics simulations illustrate a potential mechanism by which H163 modulates this transition and suggest that this equilibrium exists in the wild type enzyme. We show that other point mutations also significantly shift the equilibrium towards this state by altering conformational free energies. Unique avenues of SARS-CoV-2 research can be explored by understanding how H163 modulates this equilibrium.

PubMed: 37699927
DOI: 10.1038/s41467-023-40023-4

Experimental method

X-RAY DIFFRACTION (2.3 Å)