tetano
Editor, Senior Moderator
Elife
. 2022 Nov 22;11:e81167.
doi: 10.7554/eLife.81167.
Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography
Alberto Borsatto[SUP] 1 2 [/SUP], Obaeda Akkad[SUP] 1 2 [/SUP], Ioannis Galdadas[SUP] 1 2 [/SUP], Shumeng Ma[SUP] 3 [/SUP], Shymaa Damfo[SUP] 3 [/SUP], Shozeb Haider[SUP] 3 4 [/SUP], Frank Kozielski[SUP] 3 [/SUP], Carolina Estarellas[SUP] 5 [/SUP], Francesco Luigi Gervasio[SUP] 1 2 6 7 [/SUP]
Affiliations
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.
Keywords: SARS-CoV-2; X-ray crystallography; cryptic pockets; drug discovery; molecular biophysics; molecular dynamics; none; structural biology.
. 2022 Nov 22;11:e81167.
doi: 10.7554/eLife.81167.
Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography
Alberto Borsatto[SUP] 1 2 [/SUP], Obaeda Akkad[SUP] 1 2 [/SUP], Ioannis Galdadas[SUP] 1 2 [/SUP], Shumeng Ma[SUP] 3 [/SUP], Shymaa Damfo[SUP] 3 [/SUP], Shozeb Haider[SUP] 3 4 [/SUP], Frank Kozielski[SUP] 3 [/SUP], Carolina Estarellas[SUP] 5 [/SUP], Francesco Luigi Gervasio[SUP] 1 2 6 7 [/SUP]
Affiliations
- PMID: 36412088
- DOI: 10.7554/eLife.81167
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.
Keywords: SARS-CoV-2; X-ray crystallography; cryptic pockets; drug discovery; molecular biophysics; molecular dynamics; none; structural biology.