The 30 kb SARS-CoV-2 genome encodes for 4 structural proteins that are part of the mature viral particle, 8 accessory proteins and 15 non-structural proteins. These non-structural proteins undertake a variety of roles in virus replication, virus assembly, and evasion of the detection by host immune system. One of the non-structural proteins, Nsp15, is a uridine specific endoribonuclease. Nsp15 is conserved across coronaviruses and is employed to cleave viral RNA to evade detection by host immune defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly. However, the precise mechanism of how the enzyme recognizes and processes RNA remains poorly understood. A series of cryo-electron derived atomic models of Nsp15 of SARS-CoV-2 bound to uridine triphosphate were used to identify residues relevant in uridine recognition and to understand the catalytic mechanism of Nsp15. Reconstructions of Nsp15 in the absence of ligand and molecular dynamic simulations uncovered the capacity of adaptive changes of the endoU domain. Our findings advance understanding of how Nsp15 processes viral RNA while providing a potential structural framework for the development of new therapeutics.

Structure characterization of the uridine specific endoribonuclease, Nsp15, of SARS-Cov-2 using molecular dynamics simulations

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ACS Fall 2022

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