7Y42

Cryo-EM structure of the SARS-CoV-2 spike glycoprotein in complex with all-trans retinoic acid

7Y42 の概要

• エントリーDOI: 10.2210/pdb7y42/pdb
• EMDBエントリー: 33600
• 分子名称: Spike glycoprotein, 2-acetamido-2-deoxy-beta-D-glucopyranose, RETINOIC ACID (3 entities in total)
• 機能のキーワード: viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 379379.44

構造登録者

Xiang, Y.,Wang, L. (登録日: 2022-06-13, 公開日: 2022-07-06, 最終更新日: 2024-11-20)

主引用文献

Tong, L.,Wang, L.,Liao, S.,Xiao, X.,Qu, J.,Wu, C.,Zhu, Y.,Tai, W.,Huang, Y.,Wang, P.,Li, L.,Zhang, R.,Xiang, Y.,Cheng, G.
A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry.
Mbio, 13:e0148522-e0148522, 2022

PubMed Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19). Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all- retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. Retinoids, a group of compounds including vitamin A and its active metabolite all- retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.

PubMed: 35862773
DOI: 10.1128/mbio.01485-22

実験手法

ELECTRON MICROSCOPY (3.45 Å)