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DOI	10.1073/pnas.2021946118
	Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP
	Naydenova K.; Muir K.W.; Wu L.-F.; Zhang Z.; Coscia F.; Peet M.J.; Castro-Hartmann P.; Qian P.; Sader K.; Dent K.; Kimanius D.; Sutherland J.D.; Löwe J.; Barford D.; Russo C.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:7
英文摘要	The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	COVID-19 \| structural biology \| cryoEM \| T-705 \| drug design
语种	英语
scopus关键词	amide; enzyme inhibitor; favipiravir; pyrazine derivative; ribonucleotide; chemistry; cryoelectron microscopy; drug effect; enzymology; metabolism; procedures; single molecule imaging; ultrastructure; Amides; Coronavirus RNA-Dependent RNA Polymerase; Cryoelectron Microscopy; Enzyme Inhibitors; Pyrazines; Ribonucleotides; SARS-CoV-2; Single Molecule Imaging
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180606
作者单位	Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom; Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, 5651 GG, Netherlands
推荐引用方式 GB/T 7714	Naydenova K.,Muir K.W.,Wu L.-F.,et al. Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP[J],2021,118(7).
APA	Naydenova K..,Muir K.W..,Wu L.-F..,Zhang Z..,Coscia F..,...&Russo C.J..(2021).Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA	Naydenova K.,et al."Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).