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Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex
Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism u...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803185/ https://www.ncbi.nlm.nih.gov/pubmed/35045069 http://dx.doi.org/10.1371/journal.pcbi.1009804 |
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author | Sakuraba, Shun Xie, Qilin Kasahara, Kota Iwakiri, Junichi Kono, Hidetoshi |
author_facet | Sakuraba, Shun Xie, Qilin Kasahara, Kota Iwakiri, Junichi Kono, Hidetoshi |
author_sort | Sakuraba, Shun |
collection | PubMed |
description | Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5’-untranslated region (SL1) binds to both nsp1’s N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis. |
format | Online Article Text |
id | pubmed-8803185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88031852022-02-01 Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex Sakuraba, Shun Xie, Qilin Kasahara, Kota Iwakiri, Junichi Kono, Hidetoshi PLoS Comput Biol Research Article Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5’-untranslated region (SL1) binds to both nsp1’s N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis. Public Library of Science 2022-01-19 /pmc/articles/PMC8803185/ /pubmed/35045069 http://dx.doi.org/10.1371/journal.pcbi.1009804 Text en © 2022 Sakuraba et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sakuraba, Shun Xie, Qilin Kasahara, Kota Iwakiri, Junichi Kono, Hidetoshi Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title | Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title_full | Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title_fullStr | Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title_full_unstemmed | Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title_short | Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex |
title_sort | extended ensemble simulations of a sars-cov-2 nsp1–5’-utr complex |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803185/ https://www.ncbi.nlm.nih.gov/pubmed/35045069 http://dx.doi.org/10.1371/journal.pcbi.1009804 |
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