Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

TLDR

COVID‑19 caused by SARS‑CoV‑2 has led to global infections and deaths, yet no protein‑targeted therapies exist; the viral nucleocapsid protein is a promising antiviral target but its structure remains poorly defined. We solved the 2.7‑Å crystal structure of the SARS‑CoV‑2 nucleocapsid protein N‑terminal RNA‑binding domain, revealing a distinct electrostatic surface and a unique RNA‑binding pocket that, together with in‑vitro binding data, provides atomic‑resolution features to guide the design of specific antiviral agents.

Abstract

The outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. Currently, there is no specific viral protein-targeted therapeutics. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein remains unclear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although the overall structure is similar as other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.