Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

Gao, Y.; Yan, L.; Huang, Y.; Liu, F.; Zhao, Y.; Cao, L.; Wang, T.; Sun, Q.; Ming, Z.; Zhang, L.; Ge, J.; Zheng, L.; Zhang, Y.; Wang, H.; Zhu, Y.; Zhu, C.; Hu, T.; Hua, T.; Zhang, B.; Yang, X.; Li, J.; Yang, H.; Liu, Z.; Xu, W.; Guddat, L. W.; Wang, Q.; Lou, Z.; Rao, Z.

doi:10.1101/2020.03.16.993386

bioRxiv · 10.1101/2020.03.16.993386

Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

Gao, Y.·Yan, L.·Huang, Y.·Liu, F.·Zhao, Y.·Cao, L.·Wang, T.·Sun, Q.·Ming, Z.·Zhang, L.·Ge, J.·Zheng, L.·Zhang, Y.·Wang, H.·Zhu, Y.·Zhu, C.·Hu, T.·Hua, T.·Zhang, B.·Yang, X.·Li, J.·Yang, H.·Liu, Z.·Xu, W.·Guddat, L. W.·Wang, Q.·Lou, Z.·Rao, Z.

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Abstract

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-[A]. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified {beta}-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp. One Sentence SummaryStructure of 2019-nCov RNA polymerase.

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Gao, Y., Yan, L., Huang, Y., Liu, F., Zhao, Y., Cao, L., Wang, T., Sun, Q., Ming, Z., Zhang, L., Ge, J., Zheng, L., Zhang, Y., Wang, H., Zhu, Y., Zhu, C., Hu, T., Hua, T., Zhang, B., Yang, X., Li, J., Yang, H., Liu, Z., Xu, W., Guddat, L. W., Wang, Q., Lou, Z., Rao, Z.. 2020-03-17. Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target. https://doi.org/10.1101/2020.03.16.993386

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