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MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach
The human myxovirus resistance B (MxB) protein is an interferon-induced restriction factor that fights a wide range of viruses. We previously demonstrated that MxB binds to hepatitis C virus (HCV)-encoded non-structural protein 5A (NS5A) and inhibits HCV infection by impairing the formation of cyclo...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969595/ https://www.ncbi.nlm.nih.gov/pubmed/35369502 http://dx.doi.org/10.3389/fmicb.2022.849084 |
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author | Li, Quanjie An, Ni Yin, Xiao Zhang, Ruixin Shao, Huihan Yi, Dongrong Cen, Shan |
author_facet | Li, Quanjie An, Ni Yin, Xiao Zhang, Ruixin Shao, Huihan Yi, Dongrong Cen, Shan |
author_sort | Li, Quanjie |
collection | PubMed |
description | The human myxovirus resistance B (MxB) protein is an interferon-induced restriction factor that fights a wide range of viruses. We previously demonstrated that MxB binds to hepatitis C virus (HCV)-encoded non-structural protein 5A (NS5A) and inhibits HCV infection by impairing the formation of cyclophilin A (CypA)–NS5A complex. However, the molecular details about how the presence of MxB diminishes the binding of NS5A to CypA remain uncovered. In this study, through molecular dynamic simulations and biochemical assays, we characterized that MxB binds to NS5A domain I through its N-terminal and GTPase domains. Specifically, amino acids (aa.) 189–191 and aa. 330–334 within MxB, together with NS5A residues aa. 71–73, are crucial for MxB–NS5A interaction. Furthermore, we predicted the CypA:NS5A and CypA:NS5A:MxB complexes and calculated the per-residue energy decomposition for identified key residues of the CypA–NS5A interface. A 28% decrease in CypA–NS5A binding affinity was observed in the presence of MxB, suggesting a weakened CypA–NS5A association upon binding of MxB to NS5A, which may contribute to the MxB-mediated inhibitory effect on the formation of CypA–NS5A complex. This work provides information for the antiviral mechanism of MxB and may facilitate the discovery of new strategies to combat CypA-dependent viruses. |
format | Online Article Text |
id | pubmed-8969595 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89695952022-04-01 MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach Li, Quanjie An, Ni Yin, Xiao Zhang, Ruixin Shao, Huihan Yi, Dongrong Cen, Shan Front Microbiol Microbiology The human myxovirus resistance B (MxB) protein is an interferon-induced restriction factor that fights a wide range of viruses. We previously demonstrated that MxB binds to hepatitis C virus (HCV)-encoded non-structural protein 5A (NS5A) and inhibits HCV infection by impairing the formation of cyclophilin A (CypA)–NS5A complex. However, the molecular details about how the presence of MxB diminishes the binding of NS5A to CypA remain uncovered. In this study, through molecular dynamic simulations and biochemical assays, we characterized that MxB binds to NS5A domain I through its N-terminal and GTPase domains. Specifically, amino acids (aa.) 189–191 and aa. 330–334 within MxB, together with NS5A residues aa. 71–73, are crucial for MxB–NS5A interaction. Furthermore, we predicted the CypA:NS5A and CypA:NS5A:MxB complexes and calculated the per-residue energy decomposition for identified key residues of the CypA–NS5A interface. A 28% decrease in CypA–NS5A binding affinity was observed in the presence of MxB, suggesting a weakened CypA–NS5A association upon binding of MxB to NS5A, which may contribute to the MxB-mediated inhibitory effect on the formation of CypA–NS5A complex. This work provides information for the antiviral mechanism of MxB and may facilitate the discovery of new strategies to combat CypA-dependent viruses. Frontiers Media S.A. 2022-03-17 /pmc/articles/PMC8969595/ /pubmed/35369502 http://dx.doi.org/10.3389/fmicb.2022.849084 Text en Copyright © 2022 Li, An, Yin, Zhang, Shao, Yi and Cen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Li, Quanjie An, Ni Yin, Xiao Zhang, Ruixin Shao, Huihan Yi, Dongrong Cen, Shan MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title | MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title_full | MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title_fullStr | MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title_full_unstemmed | MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title_short | MxB Disrupts Hepatitis C Virus NS5A–CypA Complex: Insights From a Combined Theoretical and Experimental Approach |
title_sort | mxb disrupts hepatitis c virus ns5a–cypa complex: insights from a combined theoretical and experimental approach |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969595/ https://www.ncbi.nlm.nih.gov/pubmed/35369502 http://dx.doi.org/10.3389/fmicb.2022.849084 |
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