SARS-CoV-2 MT 酶 nsp14 与抑制剂 STM957 的结构揭示了与痘病毒 MT 酶 VP39 共享的抑制机制

IF 3.5 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Eva Zilecka, Martin Klima, Milan Stefek, Milan Dejmek, Radim Nencka, Evzen Boura
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引用次数: 0

摘要

Nsp14 是一种由所有冠状病毒编码的 RNA 甲基转移酶(MTase)。事实上,包括 DNA 病毒在内的许多病毒家族都编码 MT 酶,这种酶能催化 RNA 前封顶结构的甲基化,从而使病毒 RNA 完全封顶。这种封顶对病毒 RNA 的高效翻译、稳定性和免疫逃避至关重要。我们之前的研究发现了基于甲基供体--S-腺苷蛋氨酸(SAM)--化学支架的 nsp14 抑制剂,其特点是修饰的腺嘌呤碱基和取代的芳基磺酰胺。然而,这些抑制剂的结合模式仅基于对接实验。为了揭示 nsp14 抑制作用的原子细节,我们解析了 nsp14 与 STM957 结合的晶体结构。该结构揭示了 nsp14 抑制作用的原子细节,如 STM957 的 7-脱氮腺嘌呤分子与 Tyr368、Ala353 和 Phe367 形成特异性相互作用,而芳基磺酰胺分子则与 Asn388 和 Phe506 结合。7-deaza 位上的大型芳香取代基取代了腺嘌呤基附近的水分子网络。令人惊讶的是,最近在与之无关的猴痘 MT 酶 VP39 中也观察到了这种情况,7-脱氮修饰的 SAH 类似物也将水分子从活性位点附近置换出来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39

Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39

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.

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来源期刊
Journal of Structural Biology: X
Journal of Structural Biology: X Biochemistry, Genetics and Molecular Biology-Structural Biology
CiteScore
6.50
自引率
0.00%
发文量
20
审稿时长
62 days
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