The H163A Mutation Unravels an Oxidized Conformation of the SARS-CoV-2 Main Protease and Opens a New Avenue for Anti-Viral Therapeutic Design
Tran, N.; Dasari, S.; Barwell, S.; McLeod, M.; Kalyaanamoorthy, S.; Holyoak, T.; Ganesan, A.
Show abstract
The main protease of SARS-CoV-2 (Mpro) is an important target for developing COVID-19 therapeutics. Recent work has highlighted Mpros 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 a new 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 illustrated 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 can also significantly shift the equilibrium towards this state by altering conformational free energies. New therapeutic strategies against SARS-CoV-2 can be explored by understanding how H163 modulates this equilibrium.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Understanding ATP binding to DosS catalytic domain with a short ATP-lid 97%
- Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations 96%
- Oncogenic mutations in the DNA-binding domain of FOXO1 disrupt folding: quantitative insights from experiments and molecular simulations 96%
Similar papers in this journal
- Conformational modulation of a mobile loop controls catalysis in the (βα)8-barrel enzyme of histidine biosynthesis HisF 96%
- Small molecule activator of phosphatase PP2A remodels scaffold PR65 structural dynamics to promote holoenzyme assembly 96%
- Dynamical nonequilibrium molecular dynamics simulations identify allosteric sites and positions associated with drug resistance in the SARS-CoV-2 main protease 96%
Similar papers in this journal
- Conformational dynamics and asymmetry in multimodal inhibition of membrane-bound pyrophosphatases 97%
- Local frustration determines loop opening during the catalytic cycle of an oxidoreductase 96%
- The αC-β4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.