8FA1

Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with N969K mutation

8FA1 の概要

• エントリーDOI: 10.2210/pdb8fa1/pdb
• EMDBエントリー: 28947
• 分子名称: Ferritin, Dps family protein and Spike protein S2' chimera, Spike protein S2' HR2 (2 entities in total)
• 機能のキーワード: spike, hr1hr2, fusion, scaffold, viral protein
• 由来する生物種: Nostoc punctiforme PCC 73102; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 101128.72

構造登録者

Yang, K.,Brunger, A.T. (登録日: 2022-11-25, 公開日: 2023-03-29, 最終更新日: 2024-06-19)

主引用文献

Yang, K.,Wang, C.,Kreutzberger, A.J.B.,White, K.I.,Pfuetzner, R.A.,Esquivies, L.,Kirchhausen, T.,Brunger, A.T.
Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor.
Proc.Natl.Acad.Sci.USA, 120:e2300360120-e2300360120, 2023

PubMed Abstract: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that one of these mutations, N969K induces a substantial displacement in the structure of the heptad repeat 2 (HR2) backbone in the HR1HR2 postfusion bundle. Due to this mutation, fusion-entry peptide inhibitors based on the Wuhan strain sequence are less efficacious. Here, we report an Omicron-specific peptide inhibitor designed based on the structure of the Omicron HR1HR2 postfusion bundle. Specifically, we inserted an additional residue in HR2 near the Omicron HR1 K969 residue to better accommodate the N969K mutation and relieve the distortion in the structure of the HR1HR2 postfusion bundle it introduced. The designed inhibitor recovers the loss of inhibition activity of the original longHR2_42 peptide with the Wuhan strain sequence against the Omicron variant in both a cell-cell fusion assay and a vesicular stomatitis virus (VSV)-SARS-CoV-2 chimera infection assay, suggesting that a similar approach could be used to combat future variants. From a mechanistic perspective, our work suggests the interactions in the extended region of HR2 may mediate the initial landing of HR2 onto HR1 during the transition of the S protein from the prehairpin intermediate to the postfusion state.

PubMed: 36940324
DOI: 10.1073/pnas.2300360120

実験手法

ELECTRON MICROSCOPY (2.51 Å)