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X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus
Porcine epidemic diarrhea virus (PEDV) is a coronavirus that infects pigs and can have mortality rates approaching 100% in piglets, causing serious economic impact. The 3C-like protease (3CL(pro)) is essential for the coronaviral life cycle and is an appealing target for the development of therapeut...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865815/ https://www.ncbi.nlm.nih.gov/pubmed/27173881 http://dx.doi.org/10.1038/srep25961 |
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author | St. John, Sarah E. Anson, Brandon J. Mesecar, Andrew D. |
author_facet | St. John, Sarah E. Anson, Brandon J. Mesecar, Andrew D. |
author_sort | St. John, Sarah E. |
collection | PubMed |
description | Porcine epidemic diarrhea virus (PEDV) is a coronavirus that infects pigs and can have mortality rates approaching 100% in piglets, causing serious economic impact. The 3C-like protease (3CL(pro)) is essential for the coronaviral life cycle and is an appealing target for the development of therapeutics. We report the expression, purification, crystallization and 2.10 Å X-ray structure of 3CL(pro) from PEDV. Analysis of the PEDV 3CL(pro) structure and comparison to other coronaviral 3CL(pro)’s from the same alpha-coronavirus phylogeny shows that the overall structures and active site architectures across 3CL(pro)’s are conserved, with the exception of a loop that comprises the protease S(2) pocket. We found a known inhibitor of severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL(pro), (R)-16, to have inhibitor activity against PEDV 3CL(pro), despite that SARS-3CL(pro) and PEDV 3CL(pro) share only 45.4% sequence identity. Structural comparison reveals that the majority of residues involved in (R)-16 binding to SARS-3CL(pro) are conserved in PEDV-3CL(pro); however, the sequence variation and positional difference in the loop forming the S(2) pocket may account for large observed difference in IC(50) values. This work advances our understanding of the subtle, but important, differences in coronaviral 3CL(pro) architecture and contributes to the broader structural knowledge of coronaviral 3CL(pro)’s. |
format | Online Article Text |
id | pubmed-4865815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48658152016-05-23 X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus St. John, Sarah E. Anson, Brandon J. Mesecar, Andrew D. Sci Rep Article Porcine epidemic diarrhea virus (PEDV) is a coronavirus that infects pigs and can have mortality rates approaching 100% in piglets, causing serious economic impact. The 3C-like protease (3CL(pro)) is essential for the coronaviral life cycle and is an appealing target for the development of therapeutics. We report the expression, purification, crystallization and 2.10 Å X-ray structure of 3CL(pro) from PEDV. Analysis of the PEDV 3CL(pro) structure and comparison to other coronaviral 3CL(pro)’s from the same alpha-coronavirus phylogeny shows that the overall structures and active site architectures across 3CL(pro)’s are conserved, with the exception of a loop that comprises the protease S(2) pocket. We found a known inhibitor of severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL(pro), (R)-16, to have inhibitor activity against PEDV 3CL(pro), despite that SARS-3CL(pro) and PEDV 3CL(pro) share only 45.4% sequence identity. Structural comparison reveals that the majority of residues involved in (R)-16 binding to SARS-3CL(pro) are conserved in PEDV-3CL(pro); however, the sequence variation and positional difference in the loop forming the S(2) pocket may account for large observed difference in IC(50) values. This work advances our understanding of the subtle, but important, differences in coronaviral 3CL(pro) architecture and contributes to the broader structural knowledge of coronaviral 3CL(pro)’s. Nature Publishing Group 2016-05-13 /pmc/articles/PMC4865815/ /pubmed/27173881 http://dx.doi.org/10.1038/srep25961 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article St. John, Sarah E. Anson, Brandon J. Mesecar, Andrew D. X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title | X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title_full | X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title_fullStr | X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title_full_unstemmed | X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title_short | X-Ray Structure and Inhibition of 3C-like Protease from Porcine Epidemic Diarrhea Virus |
title_sort | x-ray structure and inhibition of 3c-like protease from porcine epidemic diarrhea virus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865815/ https://www.ncbi.nlm.nih.gov/pubmed/27173881 http://dx.doi.org/10.1038/srep25961 |
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