EMD-34311
A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analogue inhibitors
EMD-34311
Single-particle3.39 Å
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Map released: 11/01/2023
Last modified: 03/07/2024
Sample Organism:
Severe acute respiratory syndrome coronavirus 2
Sample: E-RTC_RNA-nsp9_GTP
Fitted models: 8gwf (Avg. Q-score: 0.29)
Deposition Authors: Yan LY, Huang YC, Rao ZH, Lou ZY
Sample: E-RTC_RNA-nsp9_GTP
Fitted models: 8gwf (Avg. Q-score: 0.29)
Deposition Authors: Yan LY, Huang YC, Rao ZH, Lou ZY
A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors.
Yan L,
Huang Y,
Ge J,
Liu Z,
Lu P
,
Huang B,
Gao S,
Wang J,
Tan L,
Ye S,
Yu F,
Lan W,
Xu S,
Zhou F,
Shi L,
Guddat LW,
Gao Y,
Rao Z,
Lou Z
(2022) Cell , 185 , 4347 - 4360.e17
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(2022) Cell , 185 , 4347 - 4360.e17
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 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.
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.