UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

Borsatto, Alberto; Akkad, Obaeda; Galdadas, Ioannis; Ma, Shumeng; Damfo, Shymaa; Haider, Shozeb; Kozielski, Frank; ... Gervasio, Francesco Luigi; + view all (2022) Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography. eLife , 11 , Article e81167. 10.7554/eLife.81167. Green open access

[thumbnail of Shozeb_elife-81167-v1.pdf]
Preview
Text
Shozeb_elife-81167-v1.pdf

Download (5MB) | Preview

Abstract

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and β-coronaviruses. 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 β-coronaviruses.

Type: Article
Title: Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.81167
Publisher version: https://doi.org/10.7554/eLife.81167
Language: English
Additional information: Copyright Borsatto et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: SARS-CoV-2, X-ray crystallography, cryptic pockets, drug discovery, molecular biophysics, molecular dynamics, none, structural biology, Humans, SARS-CoV-2, Crystallography, Viral Nonstructural Proteins, COVID-19, RNA Stability
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10160516
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item