Structural basis of SARS-CoV-2 spike protein induced by ACE2

Motivation: The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The spike (S) glycoprotein binds ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unraveling the dynamic structural features used by SARSCoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. Results: Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that j-helix (polyproline-II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like j-helix and b-strand, and conformational variations in a set of short a-helices which affect the hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structurebased intervention strategies that target SARS-CoV-2.

Automated summary

The emergence of SARS-CoV-2 has created a global health emergency due to its ability to bind with ACE2 and enter host cells. Through structural analysis, it was found that the j-helix plays a key role in facilitating the conversion of the S protein to its active form. The study also revealed conformational changes in different regions of the SARS-CoV-2-RBD, indicating a possible disulfide exchange that could be targeted for therapeutic interventions.