Volume 31, No 6, Jun 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 6, June 2021: 717-719   |  Open Access

LETTERS TO THE EDITOR

Structural basis for the different states of the spike protein of SARS-CoV-2 in complex with ACE2

Renhong Yan^1,2,* , Yuanyuan Zhang^1,2 , Yaning Li³ , Fangfei Ye^1,2 , Yingying Guo^1,2 , Lu Xia^1,2 , Xinyue Zhong^1,2 , Ximin Chi^1,2 , Qiang Zhou^1,2,*

¹Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
²Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China
³Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
These authors contributed equally: Renhong Yan, Yuanyuan Zhang, Yaning Li Correspondence: Renhong Yan(yanrenhong@westlake.edu.cn)Qiang Zhou(zhouqiang@westlake.edu.cn)

Dear Editor,

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a severe threat to global health.1 The spike (S) protein on the surface of SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as cellular receptor and mediates the fusion of the viral and the host cell membrane during infection.1,2 The activation of the S protein requires the receptor-binding domain (RBD) binding to the peptidase domain (PD) of ACE2 and the cleavage by host proteases into the N-terminal S1 subunit and the C-terminal S2 subunit.2,3,4 An additional furin cleavage site “RRAR” present in the S1/S2 cleavage region of SARS-CoV-2, which is absent in SARS-CoV that shares about 80% sequence identity with SARS-CoV-2 and caused an epidemic in 2002–2003, might help accelerate the activation of the S protein. S1 consists of the N-terminal domain (NTD), the RBD, subdomain 1 and 2 (SD1 and SD2). The RBD adopts two distinct conformations: “up” and “down”. Only the “up” RBD exposes the receptor-binding site. S2, containing the hydrophobic fusion peptide, is responsible for the viral and cell membrane fusion. The molecular mechanism underlying the activation of the S protein of SARS-CoV-2 represents a critical clue for therapeutic development. Here we report the cryo-electron microscopy (cryo-EM) structures of trimeric extracellular domain of the S protein (hereinafter referred to as S) at multiple states and conformations, including the all RBD-locked, activated, S1/S2 trypsin-cleaved, PD of ACE2-bound, and the full-length ACE2-bound states. PD binds to the trimeric S protein with consistent interface, inducing conformational change at adjacent region. The trypsin-digested S protein tends to accommodate more PD molecules. Furthermore, the structure of the S–ACE2–B0AT1 ternary complex indicates that one ACE2 dimer binds two trimeric S proteins simultaneously. These results provide clues for the mechanism of the activation of the S protein of SARS-CoV-2.

https://doi.org/10.1038/s41422-021-00490-0

FULL TEXT | PDF

Browse 742