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

Kretsch, Rachael C.; Xu, Lily; Zheludev, Ivan N.; Zhou, Xueting; Huang, Rui; Nye, Grace; Li, Shanshan; Zhang, Kaiming; Chiu, Wah; Das, Rhiju

doi:10.1073/pnas.2320493121

Title: Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses

Journal Article · 01 March 2024 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2320493121 · OSTI ID:2403416

^[1];

^[2]; Zheludev, Ivan N. ^[2];

^[2]; Huang, Rui ^[2]; Nye, Grace ^[2]; Li, Shanshan ^[3]; Zhang, Kaiming ^[3];

^[4];

^[2]

Stanford Univ., CA (United States); SLAC
Stanford Univ., CA (United States)
Univ. of Science and Technology of China, Hefei (China)
Stanford Univ., CA (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2403416

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 10 Vol. 121; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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Title: Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses

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