对维生素D受体突变的结构和功能洞察:对多态性诱导的耐药性的in-silico调查
Mohtashim Lohani1, Nizar Ahmad Khamjan2, Sajad Ahmad Dar1
1Department of Nursing, College of Nursing and Health Sciences, Jazan University, Jazan 45142, Saudi Arabia.
Biophysical chemistry
|January 17, 2026
概括
维生素D受体突变会破坏平衡和免疫功能. 计算分析揭示了这些VDR变体如何损害维生素D的结合和稳定性,导致骨和免疫系统疾病.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 计算生物学 计算生物学
背景情况:
- 维生素D受体 (VDR) 对平衡,骨健康和免疫调节至关重要.
- 在VDR中发生的突变,特别是结合体结合域 (LBD) 中发生的突变,可以导致对维生素D的抗性,并导致遗传性狂犬病和免疫失调.
研究的目的:
- 用计算方法研究VDR误解突变的结构和功能后果.
- 为了确定影响连接体结合,蛋白质稳定性和下游信号通路的特定VDR突变.
主要方法:
- 利用AlphaFold进行VDR模型生成,并结合了62个可能的致病性误解突变.
- 进行了分子对接,以评估维生素D3的结合亲和力.
- 使用分子动力学模拟 (RMSD,Rg,PCA) 和CASTp分析来评估蛋白质稳定性和结合口袋特征.
主要成果:
- 鉴定了特定突变 (R274H,R274L,H305Q) 具有稳定的构造,但减少了维生素D3的结合亲和力.
- 在其他突变中观察到显著的结构偏差,表明受体功能受损.
- 功能分析表明,对和免疫调节至关重要的信号通路的破坏.
结论:
- VDR LBD中的Missense突变损害了维生素D结合和受体稳定性,导致骨和免疫异常.
- 计算建模是识别致病性VDR变体和指导治疗策略恢复受体功能的一个有价值的工具.
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