Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, 10617, Taiwan.
Department of Agricultural Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
Commun Biol. 2021 Jan 27;4(1):123. doi: 10.1038/s42003-020-01633-6.
The macro domain is an ADP-ribose (ADPR) binding module, which is considered to act as a sensor to recognize nicotinamide adenine dinucleotide (NAD) metabolites, including poly ADPR (PAR) and other small molecules. The recognition of macro domains with various ligands is important for a variety of biological functions involved in NAD metabolism, including DNA repair, chromatin remodeling, maintenance of genomic stability, and response to viral infection. Nevertheless, how the macro domain binds to moieties with such structural obstacles using a simple cleft remains a puzzle. We systematically investigated the Middle East respiratory syndrome-coronavirus (MERS-CoV) macro domain for its ligand selectivity and binding properties by structural and biophysical approaches. Of interest, NAD, which is considered not to interact with macro domains, was co-crystallized with the MERS-CoV macro domain. Further studies at physiological temperature revealed that NAD has similar binding ability with ADPR because of the accommodation of the thermal-tunable binding pocket. This study provides the biochemical and structural bases of the detailed ligand-binding mode of the MERS-CoV macro domain. In addition, our observation of enhanced binding affinity of the MERS-CoV macro domain to NAD at physiological temperature highlights the need for further study to reveal the biological functions.
宏结构域是一个 ADP-核糖（ADPR）结合模块，被认为作为传感器来识别烟酰胺腺嘌呤二核苷酸（NAD）代谢物，包括多聚 ADPR（PAR）和其他小分子。宏结构域与各种配体的识别对于涉及 NAD 代谢的多种生物学功能很重要，包括 DNA 修复、染色质重塑、基因组稳定性的维持以及对病毒感染的反应。然而，宏结构域如何使用简单的裂隙来结合具有这种结构障碍的部分仍然是一个谜。我们通过结构和生物物理方法系统地研究了中东呼吸综合征冠状病毒（MERS-CoV）的宏结构域的配体选择性和结合特性。有趣的是，NAD 被认为不会与宏结构域相互作用，但与 MERS-CoV 宏结构域共结晶。在生理温度下的进一步研究表明，由于热可调结合口袋的容纳，NAD 与 ADPR 具有相似的结合能力。这项研究提供了 MERS-CoV 宏结构域详细配体结合模式的生化和结构基础。此外，我们观察到 MERS-CoV 宏结构域在生理温度下对 NAD 的结合亲和力增强，这突出表明需要进一步研究以揭示其生物学功能。
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