Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

TLDR

SARS‑CoV‑2 emerged in China and uses human ACE2 as its entry receptor. The study aims to determine the crystal structure of the SARS‑CoV‑2 spike C‑terminal domain bound to human ACE2. The authors solved the crystal structure of the SARS‑CoV‑2 spike C‑terminal domain in complex with human ACE2. The structure reveals that residue substitutions strengthen binding, giving higher affinity than SARS‑RBD, and that existing SARS‑CoV antibodies fail to bind, highlighting antigenic differences and informing therapeutic development.

Abstract

The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.