De novo 3D models of SARS-CoV-2 RNA elements and small-molecule-binding RNAs to guide drug discovery

Ramya Rangan; Andrew M. Watkins; Wipapat Kladwang; Rhiju Das

Several RNA regions in betacoronavirus genomes, including the 5´ UTR, the frameshifting element (FSE), and 3´ UTR, feature RNA structures with likely functional importance. These regions include a series of five conserved stem loops in the 5´ UTR, the frameshifting element along with a proposed dimerized state, a pseudoknot in the 3´ UTR proposed to form two structures, and the hypervariable region in the 3′ UTR, which includes an absolutely conserved octanucleotide and the stem-loop IIlike motif ('s2m'). An NMR structure of stem-loop 2 in the 5´ UTR has been solved, adopting a canonical CUYG tetraloop fold. 4 A crystal structure for s2m in the 3′ UTR has been solved for the original SARS virus, SARS-CoV-1. 5 With nearly complete sequence conservation compared to the SARS-CoV-2 reference genome, this structure is expected to be maintained in SARS-CoV-2. Beyond these regions, however, 3D structures for structural domains in the 5′ UTR, FSE, and 3′ UTR have not been solved.