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Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase

DOI: 10.1038/s41467-021-25166-6 DOI Help

Authors: Joseph A. Newman (University of Oxford) , Alice Douangamath (Diamond Light Source) , Setayesh Yadzani (Structural Genomics Consortium, University of Toronto) , Yuliana Yosaatmadja (Structural Genomic Consortium, Oxford) , Anthony Aimon (Diamond Light Source) , Jose Brandao-Neto (Diamond Light Source) , Louise Dunnett (Diamond Light Source) , Tyler Gorrie-Stone (Diamond Light Source) , Rachael Skyner (Diamond Light Source) , Daren Fearon (Diamond Light Source) , Matthieu Schapira (Structural Genomics Consortium, University of Toronto) , Frank Von Delft (University of Oxford; Diamond Light Source; University of Johannesburg) , Opher Gileadi (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 26998

Open Access Open Access

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.

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 14/08/2021 22:21

Documents:
s41467-021-25166-6.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening