8VAO

Simulation-driven design of prefusion stabilized SARS-CoV-2 spike S2 antigen

8VAO の概要

• エントリーDOI: 10.2210/pdb8vao/pdb
• EMDBエントリー: 43097
• 分子名称: Spike protein S2, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• 機能のキーワード: sars-cov-2, spike protein, viral fusion, viral glycoprotein, viral protein
• 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: 170961.32

構造登録者

Zhou, L.,McLellan, J.S. (登録日: 2023-12-11, 公開日: 2024-07-10, 最終更新日: 2024-11-20)

主引用文献

Nuqui, X.,Casalino, L.,Zhou, L.,Shehata, M.,Wang, A.,Tse, A.L.,Ojha, A.A.,Kearns, F.L.,Rosenfeld, M.A.,Miller, E.H.,Acreman, C.M.,Ahn, S.H.,Chandran, K.,McLellan, J.S.,Amaro, R.E.
Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens.
Nat Commun, 15:7370-7370, 2024

PubMed Abstract: The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2's usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer's opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

PubMed: 39191724
DOI: 10.1038/s41467-024-50976-9

実験手法

ELECTRON MICROSCOPY (2.8 Å)