全长的TSH受体由TSH连接体稳定
Mihaly Mezei1, Rauf Latif2, Terry F Davies2
1Department of Pharmacological Sciences, New York, NY, USA; Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Journal of molecular graphics & modelling
|February 19, 2024
概括
通过分子动力学模拟来量化甲状腺刺激激素受体 (TSHR) 灵活性. 结合TSH增强了TSHR的稳定性,特别是在链接区域,突出了受体信号结构中的配体作用.
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:
- 甲状腺刺激激素受体 (TSHR) 是一种G蛋白结合受体 (GPCR),是格雷夫斯病的主要点.
- 之前对TSHR的结构研究是有限的,只有部分的氨酸丰富域 (LRD) 结晶和不完整的全长受体的冷EM结构.
研究的目的:
- 开发一个更新的,全长的TSHR模型,使用冷EM数据和扩展分子动力学 (MD) 模拟.
- 调查TSHR的结构灵活性和TSH连体结合的影响.
主要方法:
- 使用全长TSHR的冷EM模型,将二硫化物键纳入左侧区域 (LR).
- 在脂质膜中对TSHR模型进行了广泛的3000nS分子动力学 (MD) 模拟,具有和没有TSH连接体.
- 分析了受体特性,例如结,LRD方向波动和旋转半径.
主要成果:
- MD模拟显示了TSHR的LRD和跨膜域 (TMD) 的显著稳定性.
- LR (部区域) 表现出显著的灵活性,形成过渡的次要结构.
- 结合TSH显示出结构稳定作用,特别是增加了LR的稳定性.
结论:
- 量化了TSHR结构固有的灵活性.
- 提供了TSH连体诱导TSHR稳定性的证据,特别是灵活的链接区域.
- 强调了连接体结合在决定受体的信号构造中的关键作用.
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