Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on...
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ftunivmassmm:oai:repository.escholarship.umassmed.edu:20.500.14038/51934 2023-06-06T11:52:24+02:00 Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses Zvornicanin, Sarah N Shaqra, Ala M Huang, Qiuyu J Ornelas, Elizabeth Moghe, Mallika Knapp, Mark Moquin, Stephanie Dovala, Dustin Schiffer, Celia A Kurt Yilmaz, Nese Biochemistry and Molecular Biotechnology Morningside Graduate School of Biomedical Sciences Schiffer Lab 2023-04-10T18:42:44Z https://doi.org/10.3390/v15030781 https://hdl.handle.net/20.500.14038/51934 en eng Viruses https://doi.org/10.3390/v15030781 Zvornicanin SN, Shaqra AM, Huang QJ, Ornelas E, Moghe M, Knapp M, Moquin S, Dovala D, Schiffer CA, Kurt Yilmaz N. Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses. Viruses. 2023 Mar 18;15(3):781. doi:10.3390/v15030781. PMID: 36992489; PMCID: PMC10059799. 1999-4915 doi:10.3390/v15030781 36992489 http://hdl.handle.net/20.500.14038/51934 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).; Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ Viruses 15 3 Switzerland GC376 HKU15 beluga whale coronaviruses crystal structure direct-acting antivirals drug design gammacoronavirus lufotrelvir main protease pan-coronavirus inhibitor Journal Article 2023 ftunivmassmm https://doi.org/10.3390/v1503078120.500.14038/51934 2023-04-13T17:44:19Z With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 Mpro, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 Mpro. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors. Article in Journal/Newspaper Beluga Beluga whale Beluga* University of Massachusetts, Medical School: eScholarship@UMMS |
institution |
Open Polar |
collection |
University of Massachusetts, Medical School: eScholarship@UMMS |
op_collection_id |
ftunivmassmm |
language |
English |
topic |
GC376 HKU15 beluga whale coronaviruses crystal structure direct-acting antivirals drug design gammacoronavirus lufotrelvir main protease pan-coronavirus inhibitor |
spellingShingle |
GC376 HKU15 beluga whale coronaviruses crystal structure direct-acting antivirals drug design gammacoronavirus lufotrelvir main protease pan-coronavirus inhibitor Zvornicanin, Sarah N Shaqra, Ala M Huang, Qiuyu J Ornelas, Elizabeth Moghe, Mallika Knapp, Mark Moquin, Stephanie Dovala, Dustin Schiffer, Celia A Kurt Yilmaz, Nese Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
topic_facet |
GC376 HKU15 beluga whale coronaviruses crystal structure direct-acting antivirals drug design gammacoronavirus lufotrelvir main protease pan-coronavirus inhibitor |
description |
With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 Mpro, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 Mpro. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors. |
author2 |
Biochemistry and Molecular Biotechnology Morningside Graduate School of Biomedical Sciences Schiffer Lab |
format |
Article in Journal/Newspaper |
author |
Zvornicanin, Sarah N Shaqra, Ala M Huang, Qiuyu J Ornelas, Elizabeth Moghe, Mallika Knapp, Mark Moquin, Stephanie Dovala, Dustin Schiffer, Celia A Kurt Yilmaz, Nese |
author_facet |
Zvornicanin, Sarah N Shaqra, Ala M Huang, Qiuyu J Ornelas, Elizabeth Moghe, Mallika Knapp, Mark Moquin, Stephanie Dovala, Dustin Schiffer, Celia A Kurt Yilmaz, Nese |
author_sort |
Zvornicanin, Sarah N |
title |
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
title_short |
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
title_full |
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
title_fullStr |
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
title_full_unstemmed |
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses |
title_sort |
crystal structures of inhibitor-bound main protease from delta- and gamma-coronaviruses |
publishDate |
2023 |
url |
https://doi.org/10.3390/v15030781 https://hdl.handle.net/20.500.14038/51934 |
genre |
Beluga Beluga whale Beluga* |
genre_facet |
Beluga Beluga whale Beluga* |
op_source |
Viruses 15 3 Switzerland |
op_relation |
Viruses https://doi.org/10.3390/v15030781 Zvornicanin SN, Shaqra AM, Huang QJ, Ornelas E, Moghe M, Knapp M, Moquin S, Dovala D, Schiffer CA, Kurt Yilmaz N. Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses. Viruses. 2023 Mar 18;15(3):781. doi:10.3390/v15030781. PMID: 36992489; PMCID: PMC10059799. 1999-4915 doi:10.3390/v15030781 36992489 http://hdl.handle.net/20.500.14038/51934 |
op_rights |
Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).; Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
op_doi |
https://doi.org/10.3390/v1503078120.500.14038/51934 |
_version_ |
1767958266749386752 |