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

• Published in: Nature communications Vol. 12; no. 1; pp. 4848 - 11
• Main Authors: Newman, Joseph A., Douangamath, Alice, Yadzani, Setayesh, Yosaatmadja, Yuliana, Aimon, Antony, Brandão-Neto, José, Dunnett, Louise, Gorrie-stone, Tyler, Skyner, Rachael, Fearon, Daren, Schapira, Matthieu, von Delft, Frank, Gileadi, Opher
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-08-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 631/45/535; 631/535/1266; 692/4017; 82/80; 82/83; Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Amino Acid Sequence; AMP; Antiviral agents; Apoenzymes - chemistry; Apoenzymes - metabolism; ATP; Binding Sites; Conserved sequence; COVID-19; Crystal structure; Crystallography; Crystallography, X-Ray; DNA helicase; Drug Design; Drug development; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Humanities and Social Sciences; Methyltransferases - antagonists & inhibitors; Methyltransferases - chemistry; Methyltransferases - metabolism; Models, Molecular; multidisciplinary; Pandemics; Phosphates - chemistry; Phosphates - metabolism; Protein Conformation; Proteomes; Replication; RNA Helicases - antagonists & inhibitors; RNA Helicases - chemistry; RNA Helicases - metabolism; RNA, Viral - chemistry; RNA, Viral - metabolism; SARS-CoV-2 - chemistry; SARS-CoV-2 - enzymology; Science; Science (multidisciplinary); Screening; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Structural analysis; Structure-Activity Relationship; Target recognition; Therapeutic targets; Viral diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism
• DOI: 10.1038/s41467-021-25166-6
• EISSN: 2041-1723

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.
The SARS-CoV-2 NSP13 helicase is essential for viral replication and of interest as a drug target. Here, the authors present the crystal structures of NSP13 in the apo form and bound to either phosphate or the non-hydrolysable ATP analog AMP-PNP and discuss the helicase mechanism. They also perform a crystallographic fragment screening and identify 65 bound fragments, which could help in the design of new antiviral agents.