Structure, Mechanism and Crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase

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Author(s)

Author Name

Joseph A Newman

Published 1 Project

Biochemistry

Alice Douangamath

Diamond Light Source Ltd

Published 1 Project

Biochemistry

Yuliana Yosaatmadja

University of Oxford

Published 1 Project

Biochemistry

Anthony Aimon

Published 1 Project

Biochemistry

Jose Brandao-Neto

Published 1 Project

Biochemistry

Louise Dunnett

Published 1 Project

Biochemistry

Tyler Gorrie-Stone

Published 1 Project

Biochemistry

Rachael Skyner

Diamond Light Source Ltd

Published 1 Project

Biochemistry

Daren Fearon

Diamond Light Source

Published 1 Project

Biochemistry

Matthieu Schapira

Associate Professor, University of Toronto

Published 8 Projects

Bioinformatics Biochemistry Pharmacology And Toxicology Cell Biology

Frank von Delft

Principal Investigator: Protein Crystallography, SGC, Oxford University

Published 1 Project

Biochemistry

Opher Gileadi

Principal Investigator, SGC, University of Oxford

Published 1 Project

Biochemistry

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The global COVID-19 pandemic is caused by the SARS-CoV-2 virus and has infected over 100 million and caused over 2 million fatalities worldwide at the point of writing. There is currently a lack of effective drugs to treat people infected with SARS-CoV-2. The SARS-CoV-2 Non-structural protein 13 (NSP13) is a superfamily1B helicase that has been identified as a possible target for anti-viral drugs due to its high sequence conservation and essential role in viral replication. In this study we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and the non-hydrolysable ATP analogue (AMP-PNP). Comparisons of these structures reveal details of global and local conformational changes that are induced by nucleotide binding and hydrolysis and provide insights into the helicase mechanism and possible modes of inhibition. Structural analysis reveals two pockets on NSP13 that are classified as "druggable" and include one of the most conserved sites in the entire SARS-CoV-2 proteome. To identify possible starting points for anti-viral drug development we have performed a crystallographic fragment screen against SARS-CoV-2 NSP13 helicase. The fragment screen reveals 65 fragment hits across 52 datasets, with hot spots in pockets predicted to be of functional importance, including the druggable nucleotide and nucleic acid binding sites, opening the way to structure guided development of novel antiviral agents.

Biochemistry
Biochemistry 9 Projects