Open AccessStructure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN
Author(s) -
Nicholas H. Moeller,
Ke Shi,
Özlem Demir,
Christopher Belica,
Surajit Banerjee,
Lulu Yin,
Cameron Durfee,
Rommie E. Amaro,
Hideki Aihara
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2106379119
Subject(s) - exoribonuclease , proofreading , exonuclease , biology , rna , exon , genetics , rna dependent rna polymerase , rna polymerase , polymerase , microbiology and biotechnology , dna , gene , rnase p
Significance SARS-CoV-2 nonstructural protein 14 (nsp14) exoribonuclease (ExoN) plays important roles in the proofreading during viral RNA synthesis and the evasion of host immune responses. We used X-ray crystallography, molecular dynamics simulations, and biochemical assays to investigate the structure, dynamics, and RNA-binding mechanisms of nsp14-ExoN and how its activity is regulated by another viral protein, nsp10. We also demonstrated that nsp14-ExoN can collaborate with the viral RNA polymerase to enable RNA synthesis in the presence of a chain-terminating drug, biochemically recapitulating the proofreading process. Our studies provide mechanistic insights into the functions of a key viral enzyme and a basis for future development of chemical inhibitors.