Structure and function of SARS-CoV-2 polymerase

Abstract

Coronaviruses use an RNA-dependent RNA polymerase (RdRp) to replicate and express their genome. The RdRp associates with additional non-structural proteins (nsps) to form a replication-transcription complex (RTC) that carries out RNA synthesis, capping and proofreading. However, the structure of the RdRp long remained elusive, thus limiting our understanding of coronavirus genome expression and replication. Recently, the cryo-electron microscopy structure of SARS-CoV-1 RdRp was reported. Driven by the ongoing COVID-19 pandemic, structural data on the SARS-CoV-2 polymerase and associated factors has since emerged at an unprecedented pace, with more than twenty structures released to date. This review provides an overview of the currently available coronavirus RdRp structures and outlines how they have, together with functional studies, led to a molecular understanding of the viral polymerase, its interactions with accessory factors and the mechanisms by which promising antivirals may inhibit coronavirus replication.

Figure 1

Structure of the core SARS-CoV RdRp. (a) Structure of SARS-CoV-1 RdRp (PDB 6NUR) [21^••]. The structure is shown as cartoon representation, with surface representation overlaid transparently. Coloring: Thumb – red; Palm – orange; Fingers – grey; Interface – purple; NiRAN – firebrick; nsp8 – green; nsp7 – deep blue. Zink atoms are shown as cyan spheres. (b) Structure of SARS-CoV-2 RdRp (PDB 6M71) [25^••]. Coloring and depiction as in A.

Figure 2

Structures of SARS-CoV-2 RdRp functional complexes. (a) Structure of replicating SARS-CoV-2 RdRp with RNA bound (PDB 6YYT) [24^••]. Coloring and depiction as in Figure 1. The RNA is shown without surface, with the template strand in blue and the product strand in red. (b) Structure of SARS-CoV-2 RdRp in complex with nsp13 (PDB 7CXN) [50^••]. Depiction as in (a). Nsp13 is colored in salmon. The template strand bound to nsp13 is indicated. (c) Structure of SARS-CoV-2 RdRp in complex with nsp13 and nsp9 (PDB 7CYQ) [56^•]. Depiction as in (a). Nsp9 is shown in cyan. (d) Close-up view of the interaction between nsp9 and the NiRAN domain in the structure shown in (c). Proteins are shown as cartoons and colored as in Figure 1, Figure 2c. The N-terminal ‘NNE’ motif of nsp9 and bound GDP is shown as sticks.