article · Biological and Pharmaceutical Bulletin
Middle East Respiratory Syndrome Coronavirus (MERS CoV) produces proteins that counter host innate immune defences, such as interferon responses. An examination using molecular dynamics reveals that the MERS CoV papain-like protease, a component of Non-Structural Protein 3, exhibits greater structural flexibility than its equivalent in Severe Acute Respiratory Syndrome Coronavirus (SARS CoV). This flexibility occurs in both free and ubiquitin-bound states, particularly within the ubiquitin-like domain and the catalytic fingers subdomain. Although the ubiquitin-like domain remains rigid in isolation, it becomes flexible when bound to ubiquitin, influencing downstream protein interactions and immune inhibition. Furthermore, four specific residues critical for deubiquitination are conserved across MERS CoV strains but differ from other beta coronaviruses. Along with fewer total interactions with ubiquitin, these conserved residues result in lower deubiquitinating activity, dampening the protein's direct interaction with the host immune machinery.
Understanding how coronaviruses suppress host immune defences is essential for tracking viral pathogenicity. By uncovering the structural dynamics and specific conserved residues of the MERS CoV papain-like protease, these findings clarify how the virus interacts differently with immune mechanisms compared to related coronaviruses like SARS CoV.
The computational insights into the unique structural flexibility and binding residues of MERS CoV papain-like protease provide molecular targets for antiviral drug discovery. These findings are relevant to pharmaceutical researchers and biotechnology developers designing targeted protease inhibitors. However, as this work is early-stage computational modelling, practical therapeutics or diagnostic applications remain far from market and will require extensive laboratory validation and clinical testing.
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The new emerging Middle East Respiratory Syndrome Coronavirus (MERS CoV) encodes several resistance proteins against the innate immune response of the host, including interferon (IFN) resistance. Monitoring of the status of such proteins will be important to track viral pathogenicity. In this study, molecular dynamics approaches were used to investigate MERS CoV Non-Structural Protein 3 (NSP3) specific proteins that resist host innate immunity. MERS CoV papain-like protease (Plpro) was more conformationally flexible than Severe Acute Respiratory Syndrome CoV (SARS) CoV Plpro. This flexibility was evident in either the free form or when bound with ubiquitin. There were marked changes in the root-mean-square deviation (RMSD) in the ubiquitin like domain (Ubl) and the fingers subdomain of the catalytic domain of Plpro. An interesting feature is the dynamic change in Ubl, which shows a rigid conformation in the free form of Plpro but is fully flexible upon the binding of ubiquitin. This increased flexibility could be important for the downstream effects of the interaction with other proteins and the inhibition of the innate immunity. Four major residues involved in deubiquitination, L106, P163, R168 and F265, were conserved in all MERS CoVs and differed from other Beta CoVs. These conserved CoV residues were associated with lower deubiquitinating activity and render MERS CoV Plpro with less potent deubiquitinating potential. The number of residues and total interactions with ubiquitin were lower for the MERS CoV Plpro than for the SARS CoV. These factors contribute to the lower deubiquitinating actions of MERS CoV NSP3 and its subsequently lower interaction with the host immune system.
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DOI: 10.1248/bpb.b16-00870
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