8A4Y

SARS-CoV-2 non-structural protein-1 (nsp1) in complex with N-(2,3-dihydro-1H-inden-5-yl)acetamide

8A4Y の概要

• エントリーDOI: 10.2210/pdb8a4y/pdb
• 分子名称: Host translation inhibitor nsp1, N-(2,3-dihydro-1H-inden-5-yl)acetamide (3 entities in total)
• 機能のキーワード: sars-cov-2, non-structural protein-1, fragment hit, complex, 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: 1
• 化学式量合計: 13284.38

構造登録者

Borsatto, A.,Galdadas, I.,Ma, S.,Damfo, S.,Haider, S.,Kozielski, F.,Estarellas, C.,Gervasio, F.L. (登録日: 2022-06-13, 公開日: 2022-11-23, 最終更新日: 2024-01-31)

主引用文献

Borsatto, A.,Akkad, O.,Galdadas, I.,Ma, S.,Damfo, S.,Haider, S.,Kozielski, F.,Estarellas, C.,Gervasio, F.L.
Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other beta-coronaviruses by simulations and crystallography.
Elife, 11:-, 2022

PubMed Abstract: Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α and βcoronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive molecular dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous βcoronaviruses.

PubMed: 36412088
DOI: 10.7554/eLife.81167

実験手法

X-RAY DIFFRACTION (1.099 Å)