A metal ion orients SARS-CoV-2 mRNA to ensure accurate 2′-O methylation of its first nucleotide

Thiruselvam Viswanathan, Anurag Misra, Siu-Hong Chan, Shan Qi, Nan Dai, Shailee Arya, Luis Martinez-Sobrido and Yogesh K. Gupta ()
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Thiruselvam Viswanathan: University of Texas Health at San Antonio
Anurag Misra: University of Texas Health at San Antonio
Siu-Hong Chan: New England Biolabs
Shan Qi: University of Texas Health at San Antonio
Nan Dai: New England Biolabs
Shailee Arya: University of Texas Health at San Antonio
Luis Martinez-Sobrido: Texas Biomedical Research Institute
Yogesh K. Gupta: University of Texas Health at San Antonio

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: Abstract The SARS-CoV-2 nsp16/nsp10 enzyme complex modifies the 2′-OH of the first transcribed nucleotide of the viral mRNA by covalently attaching a methyl group to it. The 2′-O methylation of the first nucleotide converts the status of mRNA cap from Cap-0 to Cap-1, and thus, helps the virus evade immune surveillance in host cells. Here, we report two structures of nsp16/nsp10 representing pre- and post-release states of the RNA product (Cap-1). We observe overall widening of the enzyme upon product formation, and an inward twisting motion in the substrate binding region upon product release. These conformational changes reset the enzyme for the next round of catalysis. The structures also identify a unique binding mode and the importance of a divalent metal ion for 2′-O methylation. We also describe underlying structural basis for the perturbed enzymatic activity of a clinical variant of SARS-CoV-2, and a previous SARS-CoV outbreak strain.

Date: 2021
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DOI: 10.1038/s41467-021-23594-y

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