The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro)
© Ali Ebrahim et al. 2022..
The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic tem-per-ature or room tem-per-ature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple tem-per-atures from cryogenic to physiological, and another at high humidity. We inter-rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for Mpro, including a mobile zinc ion inter-leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra-molecular network bridging the active site and dimer inter-face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
IUCrJ - 9(2022), Pt 5 vom: 01. Sept., Seite 682-694 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ebrahim, Ali [VerfasserIn] |
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| Links: |
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| Themen: |
Allostery |
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| Anmerkungen: |
Date Revised 31.08.2023 published: Electronic-eCollection UpdateOf: bioRxiv. 2021 Nov 07;:. - PMID 33972941 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1107/S2052252522007497 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM345889150 |
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| 500 | |a UpdateOf: bioRxiv. 2021 Nov 07;:. - PMID 33972941 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © Ali Ebrahim et al. 2022. | ||
| 520 | |a The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for the development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic tem-per-ature or room tem-per-ature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple tem-per-atures from cryogenic to physiological, and another at high humidity. We inter-rogate these data sets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a perturbation-dependent conformational landscape for Mpro, including a mobile zinc ion inter-leaved between the catalytic dyad, mercurial conformational heterogeneity at various sites including a key substrate-binding loop, and a far-reaching intra-molecular network bridging the active site and dimer inter-face. Our results may inspire new strategies for antiviral drug development to aid preparation for future coronavirus pandemics | ||
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| 650 | 4 | |a SARS-CoV-2 main protease | |
| 650 | 4 | |a X-ray crystallography | |
| 650 | 4 | |a allostery | |
| 650 | 4 | |a protein flexibility | |
| 650 | 4 | |a protein structure | |
| 650 | 4 | |a temperature-dependent | |
| 700 | 1 | |a Riley, Blake T |e verfasserin |4 aut | |
| 700 | 1 | |a Kumaran, Desigan |e verfasserin |4 aut | |
| 700 | 1 | |a Andi, Babak |e verfasserin |4 aut | |
| 700 | 1 | |a Fuchs, Martin R |e verfasserin |4 aut | |
| 700 | 1 | |a McSweeney, Sean |e verfasserin |4 aut | |
| 700 | 1 | |a Keedy, Daniel A |e verfasserin |4 aut | |
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