Understand the Emerging RNA Viruses

The Coronavirus disease 2019 (COVID-19) pandemic poses an unprecedented challenge for public health, which is caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is one of Coronaviruses. These viruses are the known RNA viruses with the largest RNA genome, ∼30 kb-long. Its replication is completed by a complex of non-structural proteins (NSP), composed of a core factor, NSP12 and two other small proteins, NSP7 and NSP8. All three factors are assembled highly dynamically in solution and NSP7 and 8 play a critical role in regulating the RNA dependent polymerase (RdRp) activity of NSP12. However, the underlying mechanism remains unknown. Here, we are using both biophysical and biochemical analysis on the interaction between NSP7 and NSP8. We obtained a structural information for the NSP7-NSP8 complex. Formation of the NSP7-NSP8 complex is mediated by two distinct oligomer interfaces, with interface I responsible for heterodimeric NSP7-NSP8 assembly, and interface II mediating the heterotetrameric interaction between the two NSP7-NSP8 dimers. Conformation guided mutation, combined with biochemical analysis, reveals a structural coupling between the two oligomer interfaces and the importance of these interfaces for the RdRp activity. We identified one NSP7 mutation that differentially affects the stability of the NSP7-NSP8 and NSP7-NSP8-NSP12 complexes, resulting in the compromised RdRP activity. This information shed light on the critical regulating role of NSP7-NSP8 on replication of SARS-CoV-2 genome, which has implications for antiviral drug development.

Learning Objectives:

1. Regulators for RNA dependent polymerase of SARS-CoV-2

2. RNA dependent polymerase of SARS-CoV-2

3. Antiviral development for SARS-CoV-2