8DV2

SARS-CoV-2 Wuhan-hu-1-Spike-RBD bound to computationally engineered ACE2 mimetic CVD293

8DV2 の概要

• エントリーDOI: 10.2210/pdb8dv2/pdb
• EMDBエントリー: 27731
• 分子名称: Spike glycoprotein, Angiotensin-converting enzyme 2,Immunoglobulin gamma-1 heavy chain fusion, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: sars-cov-2, spike, receptor-binding domain, ace2 receptor traps, antiviral protein, viral protein-antiviral protein complex, viral protein/antiviral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 249170.96

構造登録者

QCRG Structural Biology Consortium,Remesh, S.G.,Merz, G.E.,Brilot, A.F.,Chio, U.,Verba, K.A. (登録日: 2022-07-27, 公開日: 2022-08-31, 最終更新日: 2024-10-30)

主引用文献

Remesh, S.G.,Merz, G.E.,Brilot, A.F.,Chio, U.S.,Rizo, A.N.,Pospiech Jr., T.H.,Lui, I.,Laurie, M.T.,Glasgow, J.,Le, C.Q.,Zhang, Y.,Diwanji, D.,Hernandez, E.,Lopez, J.,Mehmood, H.,Pawar, K.I.,Pourmal, S.,Smith, A.M.,Zhou, F.,DeRisi, J.,Kortemme, T.,Rosenberg, O.S.,Glasgow, A.,Leung, K.K.,Wells, J.A.,Verba, K.A.
Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.
Structure, 31:253-, 2023

PubMed Abstract: The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

PubMed: 36805129
DOI: 10.1016/j.str.2023.01.009

実験手法

ELECTRON MICROSCOPY (3.5 Å)