Tertiary folds of the SL5 RNA from the 5′ proximal region of SARS-CoV-2 and related coronaviruses.

Publication date: Mar 05, 2024

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 A 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 A 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 A resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6. 5 and 8. 4 to 9. 0 A 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.

Concepts Keywords
Coronaviruses comparative structural biology
Genomic coronaviruses
Microscopy cryo-EM
Sl5s modeling
Stable viral RNA structure


Type Source Name
disease VO Betacoronavirus
disease MESH syndrome

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