Department of Pharmacy, University of Patras, 26504, Patras, Greece.
Biomol NMR Assign. 2022 Apr;16(1):9-16. doi: 10.1007/s12104-021-10052-5. Epub 2021 Oct 22.
SARS-CoV and MERS-CoV Macro Domains (MDs) exhibit topological and conformational features that resemble the nsP3b macro (or "X") domain of SARS-CoV-2. Indeed, all the three domains (SARS-CoV-2, SARS-CoV and MERS-CoV MDs) fold in a three-layer α/β/α sandwich structure, as reported by crystallographic structural investigation of SARS-CoV MD and MERS-CoV MD. These viral MDs are able to bind ADP-ribose as many other MDs from different kingdoms. They have been characterized also as de-ADP-ribosylating enzymes. For this reason, these viral macrodomains recently emerged as important drug targets since they can counteract antiviral ADP-ribosylation mediated by poly-ADP-ribose polymerase (PARPs). Even in presence of the 3D structures of SARS-CoV MD and of MERS-CoV MD, we report herein the almost complete NMR backbone (H, C, N) of SARS-CoV MD and MERS-CoV proteins in the free and ADPr bound forms, and the NMR chemical shift-based prediction of their secondary structure elements. These NMR data will help to further understanding of the atomic-level conformational dynamics of these proteins and will allow an extensive screening of small molecules as potential antiviral drugs.
SARS-CoV 和 MERS-CoV 的宏结构域（MDs）表现出与 SARS-CoV-2 的 nsP3b 宏（或“X”）结构域相似的拓扑和构象特征。事实上，正如 SARS-CoV MD 和 MERS-CoV MD 的晶体结构研究报告的那样，所有这三个结构域（SARS-CoV-2、SARS-CoV 和 MERS-CoV MDs）都折叠成三层 α/β/α 夹层结构。这些病毒 MD 能够像其他来自不同领域的许多 MD 一样结合 ADP-核糖。它们也被表征为去 ADP-核糖基酶。由于这个原因，这些病毒宏结构域最近成为重要的药物靶点，因为它们可以对抗多聚 ADP-核糖聚合酶（PARPs）介导的抗病毒 ADP-核糖基化。尽管有 SARS-CoV MD 和 MERS-CoV MD 的三维结构，但我们在此报告了 SARS-CoV MD 和 MERS-CoV 蛋白在游离和 ADPr 结合形式下的几乎完整的 NMR 骨架（H、C、N），以及它们二级结构元素的基于 NMR 化学位移的预测。这些 NMR 数据将有助于进一步了解这些蛋白质的原子级构象动力学，并允许广泛筛选小分子作为潜在的抗病毒药物。
