7QGI

Crystal structure of SARS-CoV-2 NSP14 in the absence of NSP10

7QGI の概要

• エントリーDOI: 10.2210/pdb7qgi/pdb
• 分子名称: Proofreading exoribonuclease nsp14, ZINC ION, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: nuclease, methyltransferase, sars-cov-2, nsp14, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59920.34

構造登録者

Newman, J.A.,Imprachim, N.,Yosaatmadja, Y.,Gileadi, O. (登録日: 2021-12-08, 公開日: 2022-01-26, 最終更新日: 2024-02-07)

主引用文献

Imprachim, N.,Yosaatmadja, Y.,Newman, J.A.
Crystal structures and fragment screening of SARS-CoV-2 NSP14 reveal details of exoribonuclease activation and mRNA capping and provide starting points for antiviral drug development.
Nucleic Acids Res., 51:475-487, 2023

PubMed Abstract: NSP14 is a dual function enzyme containing an N-terminal exonuclease domain (ExoN) and C-terminal Guanine-N7-methyltransferase (N7-MTase) domain. Both activities are essential for the viral life cycle and may be targeted for anti-viral therapeutics. NSP14 forms a complex with NSP10, and this interaction enhances the nuclease but not the methyltransferase activity. We have determined the structure of SARS-CoV-2 NSP14 in the absence of NSP10 to 1.7 Å resolution. Comparisons with NSP14/NSP10 complexes reveal significant conformational changes that occur within the NSP14 ExoN domain upon binding of NSP10, including helix to coil transitions that facilitate the formation of the ExoN active site and provide an explanation of the stimulation of nuclease activity by NSP10. We have determined the structure of NSP14 in complex with cap analogue 7MeGpppG, and observe conformational changes within a SAM/SAH interacting loop that plays a key role in viral mRNA capping offering new insights into MTase activity. We perform an X-ray fragment screen on NSP14, revealing 72 hits bound to sites of inhibition in the ExoN and MTase domains. These fragments serve as excellent starting point tools for structure guided development of NSP14 inhibitors that may be used to treat COVID-19 and potentially other future viral threats.

PubMed: 36546776
DOI: 10.1093/nar/gkac1207

実験手法

X-RAY DIFFRACTION (1.65 Å)