9FEH

Crystal structure of SARS-CoV-2 nsp14 methyltransferase domain in complex with the STM957 inhibitor

これはPDB形式変換不可エントリーです。

9FEH の概要

• エントリーDOI: 10.2210/pdb9feh/pdb
• 分子名称: Transcription factor ETV6,Guanine-N7 methyltransferase nsp14, ~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-[4-azanyl-5-(2-pyridin-3-ylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl]-3-cyano-~{N}-ethyl-4-methoxy-benzenesulfonamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: viral, sars-cov-2, covid-19, methyltransferase, rna cap, inhibitor, stm957, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36181.45

構造登録者

Zilecka, E.,Klima, M.,Boura, E. (登録日: 2024-05-20, 公開日: 2024-08-28, 最終更新日: 2024-09-04)

主引用文献

Zilecka, E.,Klima, M.,Stefek, M.,Dejmek, M.,Nencka, R.,Boura, E.
Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39.
J Struct Biol X, 10:100109-100109, 2024

PubMed Abstract: Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses. In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA. This capping is crucial for efficient viral RNA translation, stability, and immune evasion. Our previous research identified nsp14 inhibitors based on the chemical scaffold of its methyl donor - the S-adenosyl methionine (SAM) - featuring a modified adenine base and a substituted arylsulfonamide. However, the binding mode of these inhibitors was based only on docking experiments. To uncover atomic details of nsp14 inhibition we solved the crystal structure of nsp14 bound to STM957. The structure revealed the atomic details of nsp14 inhibition such that the 7-deaza-adenine moiety of STM957 forms specific interactions with Tyr368, Ala353, and Phe367, while the arylsulfonamide moiety engages with Asn388 and Phe506. The large aromatic substituent at the 7-deaza position displaces a network of water molecules near the adenine base. Surprisingly, this was recently observed in the case of an unrelated monkeypox MTase VP39, where the 7-deaza modified SAH analogs also displaced water molecules from the vicinity of the active site.

PubMed: 39188530
DOI: 10.1016/j.yjsbx.2024.100109

実験手法

X-RAY DIFFRACTION (1.99 Å)