Selected article for: "cryo em and RNA template"
Author: Shannon, Ashleigh; Fattorini, Véronique; Sama, Bhawna; Selisko, Barbara; Feracci, Mikael; Falcou, Camille; Gauffre, Pierre; Kazzi, Priscila El; Decroly, Etienne; Rabah, Nadia; Alvarez, Karine; Eydoux, Cécilia; Guillemot, Jean-Claude; Debart, Françoise; Vasseur, Jean-Jacques; Noel, Mathieu; Moussa, Adel; Good, Steven; Lin, Kai; Sommadossi, Jean-Pierre; Zhu, Yingxiao; Yan, Xiaodong; Shi, Hui; Ferron, François; Canard, Bruno
Title: Protein-primed RNA synthesis in SARS-CoVs and structural basis for inhibition by AT-527
  • Cord-id: q25746hs
  • Document date: 2021_3_23
    • ID: q25746hs
    Snippet: How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and −2 Nidovirus RdRp-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA
    Document: How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and −2 Nidovirus RdRp-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA synthesis at the precise genome-poly(A) junction. The guanosine analogue 5’-triphosphate AT-9010 (prodrug: AT-527) tightly binds to the NiRAN and inhibits both nsp8-labeling and the initiation of RNA synthesis. A 2.98 Å resolution Cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 /RNA/NTP quaternary complex shows AT-9010 simultaneously binds to both NiRAN and RdRp active site of nsp12, blocking their respective activities. AT-527 is currently in phase II clinical trials, and is a potent inhibitor of SARS-CoV-1 and −2, representing a promising drug for COVID-19 treatment.

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