7DMU

Structure of SARS-CoV-2 spike receptor-binding domain complexed with high affinity ACE2 mutant 3N39

7DMU の概要

• エントリーDOI: 10.2210/pdb7dmu/pdb
• 分子名称: Angiotensin-converting enzyme 2, Spike protein S1, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: sars-cov-2, covid-19, ace2, viral protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 196426.79

構造登録者

Arimori, T.,Takagi, J. (登録日: 2020-12-07, 公開日: 2020-12-23, 最終更新日: 2024-10-16)

主引用文献

Higuchi, Y.,Suzuki, T.,Arimori, T.,Ikemura, N.,Mihara, E.,Kirita, Y.,Ohgitani, E.,Mazda, O.,Motooka, D.,Nakamura, S.,Sakai, Y.,Itoh, Y.,Sugihara, F.,Matsuura, Y.,Matoba, S.,Okamoto, T.,Takagi, J.,Hoshino, A.
Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2.
Nat Commun, 12:3802-3802, 2021

PubMed Abstract: SARS-CoV-2 has mutated during the global pandemic leading to viral adaptation to medications and vaccinations. Here we describe an engineered human virus receptor, ACE2, by mutagenesis and screening for binding to the receptor binding domain (RBD). Three cycles of random mutagenesis and cell sorting achieved sub-nanomolar affinity to RBD. Our structural data show that the enhanced affinity comes from better hydrophobic packing and hydrogen-bonding geometry at the interface. Additional disulfide mutations caused the fixing of a closed ACE2 conformation to avoid off-target effects of protease activity, and also improved structural stability. Our engineered ACE2 neutralized SARS-CoV-2 at a 100-fold lower concentration than wild type; we also report that no escape mutants emerged in the co-incubation after 15 passages. Therapeutic administration of engineered ACE2 protected hamsters from SARS-CoV-2 infection, decreased lung virus titers and pathology. Our results provide evidence of a therapeutic potential of engineered ACE2.

PubMed: 34155214
DOI: 10.1038/s41467-021-24013-y

実験手法

X-RAY DIFFRACTION (3.2 Å)