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. 2020 May 15;368(6492):779-782.
doi: 10.1126/science.abb7498. Epub 2020 Apr 10.

Structure of the RNA-dependent RNA Polymerase From COVID-19 Virus

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Free PMC article

Structure of the RNA-dependent RNA Polymerase From COVID-19 Virus

Yan Gao et al. Science. .
Free PMC article

Abstract

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.

Figures

Fig. 1
Fig. 1. Structure of COVID-19 virus nsp12-nsp7-nsp8 complex.
(A) Domain organization of COVID-19 virus nsp12. The interdomain borders are labeled with residue numbers. The N-terminal portion with no cryo-EM map density and the C-terminal residues that cannot be observed in the map are not included in the assignment. The polymerase motifs are colored as follows: motif A, yellow; motif B, red; motif C, green; motif D, violet; motif E, cyan; motif F, blue; and motif G, light brown. (B) Ribbon diagram of COVID-19 virus nsp12 polypeptide chain in three perpendicular views. Domains are colored the same as in (A). The individual nsp8 (nsp8-1) bound to nsp12 and that in the nsp7-nsp8 pair (nsp8-2) are shown in gray; the nsp7 is in pink. The bottom left panel shows an overview of the cryo-EM reconstruction of the nsp12-nsp7-nsp8 complex.
Fig. 2
Fig. 2. Structure of N-terminal NiRAN domain and β hairpin.
(A) Overall structure of the N-terminal NiRAN domain and β hairpin of COVID-19 virus nsp12. The N-terminal NiRAN domain and β hairpin of COVID-19 virus nsp12 are shown as yellow and cyan cartoons, respectively, whereas the other regions of COVID-19 virus nsp12 are shown as a molecular surface with the same color scheme used in Fig. 1. The NiRAN domain of SARS-CoV nsp12 is superimposed to its counterpart in COVID-19 virus nsp12 and is shown in purple. (B) Key interactions between the β hairpin and other domains. The β hairpin is shown as a cyan tube with its key residues in stick mode. These have the closest contacts with other domains of COVID-19 virus nsp12. The interacting residues in the palm and fingers subdomain of the RdRp domain and the NiRAN domain are identified by the labels. Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
Fig. 3
Fig. 3. The RdRp core region.
(A to C) Structural comparison of COVID-19 virus nsp12 (A), HCV ns5b (PDB ID: 4WTG) (13) (B), and PV 3Dpol (PDB ID: 3OLB) (14) (C). The three structures are displayed in the same orientation. The polymerase motifs (motifs A to G) have the same color scheme used in Fig. 1A. (D) The template entry, NTP entry, and product hybrid exit paths in COVID-19 virus nsp12 are labeled in slate, deep teal, and orange colors, respectively. Two catalytic manganese ions (black spheres), pp-sofosbuvir (dark green spheres for carbon atoms), and primer template (orange) from the structure of HCV ns5b in complex pp-sofosbuvir (PDB ID: 4WTG) (13) are superposed to COVID-19 virus nsp12 to indicate the catalytic site and nucleotide binding position.
Fig. 4
Fig. 4. Incorporation model of remdesivir in COVID-19 virus nsp12.
(A) The polymerase motifs are colored as in Fig. 3. Superposition of the structure of HCV ns5b in complex with pp-sofosbuvir (PDB ID: 4WTG) (13) with COVID-19 virus nsp12 shows the possible positions of the two catalytic ions (purple spheres), the priming nucleotide (U 0), template strand, and the incoming pp-remdesivir in nsp12. (B to E) Structure comparison of HCV apo ns5b or its complex with UDP and pp-sofosbuvir with the COVID-19 virus nsp12.

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