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. 2025 Jun 5;33(6):1027-1039.e4.
doi: 10.1016/j.str.2025.03.009. Epub 2025 Apr 11.

Structural insights into the assembly and regulation of 2'-O RNA methylation by SARS-CoV-2 nsp16/nsp10

Anurag Misra  1 , R Rahisuddin  1 , Manish Parihar  2 , Shailee Arya  2 , Thiruselvam Viswanathan  1 , Nathaniel Jackson  3 , Shan Qi  1 , Siu-Hong Chan  4 , Reuben S Harris  5 , Luis Martinez-Sobrido  3 , Yogesh K Gupta  6
Affiliations

Structural insights into the assembly and regulation of 2'-O RNA methylation by SARS-CoV-2 nsp16/nsp10

Anurag Misra et al. Structure. .

Abstract

2'-O-ribose methylation of the first transcribed base (adenine or A1 in SARS-CoV-2) of viral RNA mimics host RNAs and subverts the innate immune response. How nsp16, with partner nsp10, assembles on the 5'-end of SARS-CoV-2 mRNA to methylate A1 is not fully understood. We present a ∼2.4 Å crystal structure of the heterotetrameric complex formed by the cooperative assembly of two nsp16/nsp10 heterodimers with one 10-mer Cap-1 RNA (product) bound to each. An aromatic zipper-like motif in nsp16 and the N-terminal regions of nsp10 and nsp16 orchestrate oligomeric assembly for efficient methylation. The front catalytic pocket of nsp16 stabilizes the upstream portion of the RNA while downstream RNA remains unresolved, likely due to flexibility. An inverted nsp16 dimer extends the positively charged surface for longer RNA to influence catalysis. Additionally, a non-specific nucleotide-binding pocket on the backside of nsp16 plays a critical role in catalysis, contributing to enzymatic activity.

Keywords: Nsp10; Nsp16; RNA capping; RNA methylation.

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Conflict of interest statement

Declaration of interests Y.K.G. is the founder of Atomic Therapeutics. S.-H.C. is an employee of New England Biolabs. These affiliations do not affect the authors’ impartiality, adherence to journal standards and policies, or data availability.

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