Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase
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Abstract
There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two “druggable” pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.
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SciScore for 10.1101/2021.03.15.435326: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For overexpression the plasmid was transformed into E. coli BL21 Rosetta2 cells. Rosetta2suggested: NoneSoftware and Algorithms Sentences Resources Refinement was performed using PHENIX REFINE(33). PHENIXsuggested: (Phenix, RRID:SCR_014224)Refinement was performed using REFMAC(35) or BUSTER. BUSTERsuggested: (BUSTER, RRID:SCR_015653)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section …SciScore for 10.1101/2021.03.15.435326: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For overexpression the plasmid was transformed into E. coli BL21 Rosetta2 cells. Rosetta2suggested: NoneSoftware and Algorithms Sentences Resources Refinement was performed using PHENIX REFINE(33). PHENIXsuggested: (Phenix, RRID:SCR_014224)Refinement was performed using REFMAC(35) or BUSTER. BUSTERsuggested: (BUSTER, RRID:SCR_015653)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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