tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2024 Mar 5;121(10):e2320493121.
doi: 10.1073/pnas.2320493121. Epub 2024 Mar 1. Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses
Rachael C Kretsch[SUP] 1 [/SUP], Lily Xu[SUP] 2 [/SUP], Ivan N Zheludev[SUP] 3 [/SUP], Xueting Zhou[SUP] 4 [/SUP], Rui Huang[SUP] 3 [/SUP], Grace Nye[SUP] 3 [/SUP], Shanshan Li[SUP] 5 [/SUP], Kaiming Zhang[SUP] 5 [/SUP], Wah Chiu[SUP] 1 4 6 [/SUP], Rhiju Das[SUP] 1 3 7 [/SUP]
Affiliations
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.
Keywords: comparative structural biology; coronaviruses; cryo-EM; modeling; viral RNA structure.
. 2024 Mar 5;121(10):e2320493121.
doi: 10.1073/pnas.2320493121. Epub 2024 Mar 1. Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses
Rachael C Kretsch[SUP] 1 [/SUP], Lily Xu[SUP] 2 [/SUP], Ivan N Zheludev[SUP] 3 [/SUP], Xueting Zhou[SUP] 4 [/SUP], Rui Huang[SUP] 3 [/SUP], Grace Nye[SUP] 3 [/SUP], Shanshan Li[SUP] 5 [/SUP], Kaiming Zhang[SUP] 5 [/SUP], Wah Chiu[SUP] 1 4 6 [/SUP], Rhiju Das[SUP] 1 3 7 [/SUP]
Affiliations
- PMID: 38427602
- DOI: 10.1073/pnas.2320493121
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.
Keywords: comparative structural biology; coronaviruses; cryo-EM; modeling; viral RNA structure.