在类风湿性关节炎中解码致病性MMP9变体,使用计算和分子动力学方法
Maria Sharif1, Kashaf Rasool1, Peter John2
1Department of Biomedicine, Atta-ur-Rahman School of Applied Biosciences(ASAB), National University of Sciences & Technology(NUST), Islamabad, 44000, Pakistan.
Scientific reports
|September 30, 2025
概括
这项研究确定了与类风湿性关节炎 (RA) 严重程度相关的矩阵金属蛋白酶-9 (MMP9) 基因中的有害变异. 这些遗传变化影响MMP9的功能和稳定性,为RA遗传查和治疗提供了洞察力.
科学领域:
- 遗传学和分子生物学
- 类风湿病学 类风湿病学
- 计算生物学 计算生物学
背景情况:
- 风湿性关节炎 (RA) 是一种慢性自身免疫性疾病,导致关节炎症和退化.
- 矩阵金属蛋白酶-9 (MMP9) 在细胞外矩阵重塑中至关重要,其高水平与RA严重程度相关.
研究的目的:
- 识别和描述MMP9基因的功能和致病变体.
- 评估这些MMP9变异对RA易感性和严重性的影响.
主要方法:
- 利用计算工具在MMP9.9中识别有害的非同义单核酸多态 (nsSNP).
- 使用计算模型 (ERRAT,VERIFY3D,QMEAN) 评估了nsSNP的保护,蛋白质结构/功能影响和稳定性.
- 进行了分子动力学模拟,分子对接和基因-基因相互作用分析.
主要成果:
- 在MMP9催化区域中确定了九个破坏性的误解nsSNP,所有这些都高度保存.
- 发现大多数突变降低了蛋白质的稳定性和功能域的改变;Y262C丢失了酸化部位.
- 分子动力学模拟显示变体的不稳定性增加,Y262C,P180L,G438A和D434N呈现高RMSD值.
结论:
- 在MMP9中,致病性nsSNP显著影响其结构和功能,导致RA.
- 这些发现对于RA患者的遗传查很重要.
- 已识别的MMP9变异可能代表了类风湿性关节炎的潜在治疗点.
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