Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON N1G 5C9, Canada.
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada.
Int J Mol Sci. 2021 Feb 5;22(4):1604. doi: 10.3390/ijms22041604.
Trichothecenes are the most prevalent mycotoxins contaminating cereal grains. Some of them are also considered as the virulence factors of head blight disease. However, the mechanism behind the structure-activity relationship for trichothecenes remains unexplained. Filling this information gap is a crucial step for developing strategies to manage this large family of mycotoxins in food and feed. Here, we perform an in-depth re-examination of the existing structures of ribosome complexed with three different trichothecenes. Multiple binding interactions between trichothecenes and 25S rRNA, including hydrogen bonds, nonpolar pi stacking interactions and metal ion coordination interactions, are identified as important binding determinants. These interactions are mainly contributed by the key structural elements to the toxicity of trichothecenes, including the oxygen in the 12,13-epoxide ring and a double bond between C and C. In addition, the C-OH group also participates in binding. The comparison of three trichothecenes binding to the ribosome, along with their binding pocket architecture, suggests that the substitutions at different positions impact trichothecenes binding in two different patterns. Moreover, the binding of trichothecenes induced conformation changes of several nucleotide bases in 25S rRNA. This then provides a structural framework for understanding the structure-activity relationships apparent in trichothecenes. This study will facilitate the development of strategies aimed at detoxifying mycotoxins in food and feed and at improving the resistance of cereal crops to fungal diseases.
三哩醇是污染谷物的最普遍的霉菌毒素之一。其中一些也被认为是赤霉病的毒力因子。然而，三哩醇结构-活性关系的机制仍未得到解释。填补这一信息空白是制定管理食品和饲料中这一大类霉菌毒素策略的关键步骤。在这里，我们对与三种不同三哩醇结合的核糖体的现有结构进行了深入的重新检查。三哩醇与 25S rRNA 之间存在多种结合相互作用，包括氢键、非极性π堆积相互作用和金属离子配位相互作用，这些相互作用被确定为重要的结合决定因素。这些相互作用主要由三哩醇毒性的关键结构元素贡献，包括 12,13-环氧化物环中的氧和 C 和 C 之间的双键。此外，C-OH 基团也参与结合。三种三哩醇与核糖体的结合比较，以及它们的结合口袋结构，表明不同位置的取代以两种不同的模式影响三哩醇的结合。此外，三哩醇的结合诱导了 25S rRNA 中几个核苷酸碱基的构象变化。这为理解三哩醇中明显的结构-活性关系提供了一个结构框架。这项研究将有助于制定旨在解毒食品和饲料中霉菌毒素和提高谷物对真菌病抗性的策略。
