6XRZ

The 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome

Summary for 6XRZ

• Entry DOI: 10.2210/pdb6xrz/pdb
• EMDB information: 22296 22297
• Descriptor: Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome (1 entity in total)
• Functional Keywords: frameshift stimulation element, sars-cov-2, covid-19, rna
• Biological source: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 28285.66

Authors

Zhang, K.,Zheludev, I.,Hagey, R.,Wu, M.,Haslecker, R.,Hou, Y.,Kretsch, R.,Pintilie, G.,Rangan, R.,Kladwang, W.,Li, S.,Pham, E.,Souibgui, C.,Baric, R.,Sheahan, T.,Souza, V.,Glenn, J.,Chiu, W.,Das, R. (deposition date: 2020-07-14, release date: 2020-08-19, Last modification date: 2024-03-06)

Primary citation

Zhang, K.,Zheludev, I.N.,Hagey, R.J.,Wu, M.T.,Haslecker, R.,Hou, Y.J.,Kretsch, R.,Pintilie, G.D.,Rangan, R.,Kladwang, W.,Li, S.,Pham, E.A.,Bernardin-Souibgui, C.,Baric, R.S.,Sheahan, T.P.,D Souza, V.,Glenn, J.S.,Chiu, W.,Das, R.
Cryo-electron Microscopy and Exploratory Antisense Targeting of the 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome.
Biorxiv, 2020

PubMed Abstract: Drug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome . The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides . To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 Å, presents a topologically complex fold in which the 5' end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules.

PubMed: 32743589
DOI: 10.1101/2020.07.18.209270

Experimental method

ELECTRON MICROSCOPY (6.9 Å)