Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase
By Quan Wang, Jiqin Wu, Haofeng Wang, Yan Gao, Qiaojie Liu, A. Mu, W. Ji, Liming Yan, Yan Zhu, Chen Zhu and 16 more. 2020
593 citations recorded by the source corpus.
Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
Subfields: Cardiology and Cardiovascular Medicine, Infectious Diseases
Citations in the corpus
- Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “…domain (RBD) in complex with ACE2 defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity (Lan et al., 2020; Shang et al., 2020; Wang et al., 2020b; Yan et al., 2020).”
- Molecular Architecture of the SARS-CoV-2 Virus (2020, unknown): “The S protein binds to the cellular surface receptor angiotensin-converting enzyme-2 (ACE2) through the receptor binding domain (RBD), an essential step for membrane fusion (Hoffmann et al., 2020; Lan et al., 2020; Shang et al., 2020; Wang et al., 2020; Yan et al., 2020; Zhou et al., 2020).”