Journal: Cell / Year: 2022 Title: A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors. Authors: Liming Yan / Yucen Huang / Ji Ge / Zhenyu Liu / Pengchi Lu / Bo Huang / Shan Gao / Junbo Wang / Liping Tan / Sihan Ye / Fengxi Yu / Weiqi Lan / Shiya Xu / Feng Zhou / Lei Shi / Luke W Guddat ...Authors: Liming Yan / Yucen Huang / Ji Ge / Zhenyu Liu / Pengchi Lu / Bo Huang / Shan Gao / Junbo Wang / Liping Tan / Sihan Ye / Fengxi Yu / Weiqi Lan / Shiya Xu / Feng Zhou / Lei Shi / Luke W Guddat / Yan Gao / Zihe Rao / Zhiyong Lou / Abstract: Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The ...Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.
RNA-directedRNApolymerase / RNA-dependent RNA polymerase / Pol / RdRp / Non-structural protein 12 / nsp12
Mass: 106780.977 Da / Num. of mol.: 1 / Fragment: UNP residues 4393-5324 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0DTD1, RNA-directed RNA polymerase
#6: Protein
Helicase / / Hel / Non-structural protein 13 / nsp13
Mass: 66930.531 Da / Num. of mol.: 2 / Fragment: UNP residues 5325-5925 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0DTD1
-
Non-structural protein ... , 3 types, 4 molecules BDCG
#2: Protein
Non-structuralprotein8 / nsp8
Mass: 21903.047 Da / Num. of mol.: 2 / Fragment: UNP residues 3943-4140 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0DTD1
#3: Protein
Non-structuralprotein7 / nsp7
Mass: 9248.804 Da / Num. of mol.: 1 / Fragment: UNP residues 3860-3942 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0DTC1
#7: Protein
Non-structuralprotein9 / nsp9
Mass: 12697.337 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Uridine monophosphate bound to to N-terminal of chain G Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2 Gene: rep, 1a-1b / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0DTD1
-
RNA chain , 2 types, 2 molecules IJ
#4: RNA chain
RNA (25-MER)
Mass: 8172.932 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#5: RNA chain
template
Mass: 10443.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
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