通过马尔科夫状态模型透露O-GlcNAc转移酶对UDP-GlcNAc识别的构造动态
Jiaqi Tian1, Xin Dong1, Tianshuo Wu1
1School of Medical Informatics and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
International journal of biological macromolecules
|November 28, 2023
概括
与O相关的N-乙糖胺 (O-GlcNAc) 转移酶 (OGT) 通过四个关键状态来识别UDP-GlcNAc. 这项分子动力学研究揭示了结合机制,对于理解O-GlcNAc糖化和药物开发至关重要.
科学领域:
- 生物化学和分子生物学
- 葡萄糖科学 (Glycoscience) 是一种科学.
- 计算生物学 计算生物学
背景情况:
- 与O相关的N-乙糖胺 (O-GlcNAc) 糖化是一种重要的翻译后修饰,影响着许多生理和病理过程.
- O-GlcNAc转移酶 (OGT) 是唯一的酶,通过将GlcNAc从UDP-GlcNAc转移到蛋白质基质来催化O-GlcNAc糖化.
- 虽然晶体结构提供了UDP-GlcNAc与OGT相互作用的见,但对原子层次的动态识别过程缺乏详细的理解.
研究的目的:
- 阐明了OGT对UDP-GlcNAc识别的原子级构造动态.
- 描述OGT-UDP-GlcNAc绑定过程中涉及的关键的超稳定状态和时间表.
- 研究特定氨基酸残留物,如K842在基质识别机制中的作用.
主要方法:
- 广泛的全原子分子动力学 (MD) 模拟总计大约9微秒.
- 构建一个马尔科夫状态模型来分析模拟数据并识别关键的结构状态.
- 变异型MD模拟以评估基质结合中的特定残留物的功能意义,如K842.
主要成果:
- 由OGT进行的UDP-GlcNAc识别过程涉及四个关键的元稳定状态,发生在约10微秒的时间尺度上.
- 酸盐部分 (P2O52-) 最初通过盐桥和键与OGT活性部位结合,然后结合尿素和GlcNAc.
- 分子动力学模拟证实了素842 (K842) 在与酸盐组形成盐桥的作用,这对于UDP-GlcNAc结合至关重要.
结论:
- 本研究提供了一个全面的,原子层面的理解 UDP-GlcNAc 识别机制由 OGT.
- 已确定的转移稳定状态和结合动态为O-GlcNAc糖化调节提供了关键的见解.
- 这些发现可以为针对涉及OGT失调的疾病的向治疗方法的合理设计提供信息.
更多相关视频
07:40Author Spotlight: Unveiling the Structural and Dynamic Aspects of Glycan Molecular Recognition
Published on: May 17, 2024
1.3K
05:28Demonstration of Heterologous Complexes formed by Golgi-Resident Type III Membrane Proteins using Split Luciferase Complementation Assay
Published on: September 10, 2020
2.4K
相关概念视频
01:29Protein Folding Quality Check in the RER
3.7K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.7K
01:24Oligosaccharide Assembly
2.9K
Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
Multiple sugar molecules that may or may...
2.9K