Severe acute respiratory syndrome coronavirus RNA-dependent RNA polymerase, also known as non-structural protein 12, and similar proteins from betacoronaviruses in the B lineage: responsible for replication and transcription of the viral RNA genome
This group contains the RNA-dependent RNA polymerase (RdRp) of Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 (also known as 2019 novel CoV (2019-nCoV) or COVID-19 virus), and similar proteins from betacoronaviruses in the sarbecovirus subgenera (B lineage). CoVs utilize a multi-subunit replication/transcription machinery. A set of non-structural proteins (Nsps) generated as cleavage products of the ORF1a and ORF1ab viral polyproteins assemble to facilitate viral replication and transcription. A key component, the RNA-dependent RNA polymerase (RdRp, also known as Nsp12), catalyzes the synthesis of viral RNA and thus plays a central role in the replication and transcription cycle of CoV, possibly interacting with its co-factors, Nsp7 and Nsp8. RdRp is therefore considered a primary target for nucleotide analog antiviral inhibitors such as remdesivir, which shows potential for the treatment of SARS-CoV-2 viral infections. The structure of SARS-CoV-2 Nsp12 contains a RdRp domain as well as a large N-terminal extension that adopts a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) architecture. Recent studies have shown that the SARS-CoV-2 RdRp requires two iron-sulfur clusters to function optimally. Earlier studies had mistakenly identified these iron-sulfur cluster binding sites for zinc-binding sites, likely because iron-sulfur clusters degrade easily under standard experimental conditions.The RdRp domain displays a right hand with three functional subdomains, called fingers, palm, and thumb. All RdRps contain conserved polymerase motifs (A-G), located in the palm (A-E motifs) and finger (F-G) subdomains. All these motifs have been implicated in RdRp fidelity such as processes of correct incorporation and reorganization of nucleotides.
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