Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses
Coronavirus genomes sequester their start codons within stem-loop 5 (SL5), a structured, 5' genomic RNA element. In most alpha- and betacoronaviruses, the secondary structure of SL5 is predicted to contain a four-way junction of helical stems, some of which are capped with UUYYGU hexaloops. Here, using cryogenic electron microscopy (cryo-EM) and computational modeling with biochemically determined secondary structures, we present three-dimensional structures of SL5 from six coronaviruses. The SL5 domain of betacoronavirus severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV-2), resolved at 4.7 Å resolution, exhibits a T-shaped structure, with its UUYYGU hexaloops at opposing ends of a coaxial stack, the T's "arms." Further analysis of SL5 domains from SARS-CoV-1 and MERS (7.1 and 6.4 to 6.9 Å resolution, respectively) indicate that the junction geometry and inter-hexaloop distances are conserved features across these human-infecting betacoronaviruses. The MERS SL5 domain displays an additional tertiary interaction, which is also observed in the non-human-infecting betacoronavirus BtCoV-HKU5 (5.9 to 8.0 Å resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6.5 and 8.4 to 9.0 Å resolution, respectively), exhibit the same coaxial stacks, including the UUYYGU-capped arms, but with a phylogenetically distinct crossing angle, an X-shape. As such, all SL5 domains studied herein fold into stable tertiary structures with cross-genus similarities and notable differences, with implications for potential protein-binding modes and therapeutic targets.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 10 vom: 05. März, Seite e2320493121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kretsch, Rachael C [VerfasserIn] |
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| Links: |
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| Themen: |
63231-63-0 |
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| Anmerkungen: |
Date Completed 04.03.2024 Date Revised 14.03.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Nov 27;:. - PMID 38076883 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2320493121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses |
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| 500 | |a UpdateOf: bioRxiv. 2023 Nov 27;:. - PMID 38076883 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Coronavirus genomes sequester their start codons within stem-loop 5 (SL5), a structured, 5' genomic RNA element. In most alpha- and betacoronaviruses, the secondary structure of SL5 is predicted to contain a four-way junction of helical stems, some of which are capped with UUYYGU hexaloops. Here, using cryogenic electron microscopy (cryo-EM) and computational modeling with biochemically determined secondary structures, we present three-dimensional structures of SL5 from six coronaviruses. The SL5 domain of betacoronavirus severe-acute-respiratory-syndrome-related coronavirus 2 (SARS-CoV-2), resolved at 4.7 Å resolution, exhibits a T-shaped structure, with its UUYYGU hexaloops at opposing ends of a coaxial stack, the T's "arms." Further analysis of SL5 domains from SARS-CoV-1 and MERS (7.1 and 6.4 to 6.9 Å resolution, respectively) indicate that the junction geometry and inter-hexaloop distances are conserved features across these human-infecting betacoronaviruses. The MERS SL5 domain displays an additional tertiary interaction, which is also observed in the non-human-infecting betacoronavirus BtCoV-HKU5 (5.9 to 8.0 Å resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6.5 and 8.4 to 9.0 Å resolution, respectively), exhibit the same coaxial stacks, including the UUYYGU-capped arms, but with a phylogenetically distinct crossing angle, an X-shape. As such, all SL5 domains studied herein fold into stable tertiary structures with cross-genus similarities and notable differences, with implications for potential protein-binding modes and therapeutic targets | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a comparative structural biology | |
| 650 | 4 | |a coronaviruses | |
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| 700 | 1 | |a Xu, Lily |e verfasserin |4 aut | |
| 700 | 1 | |a Zheludev, Ivan N |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xueting |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Nye, Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Kaiming |e verfasserin |4 aut | |
| 700 | 1 | |a Chiu, Wah |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Rhiju |e verfasserin |4 aut | |
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