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在构成性活跃的雌激素受体内调查螺旋12动态,使用双部分四氨显示器

Lasantha R Sendanayake¹, Ranju Pokhrel¹, Justin M Holub²

¹Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA.

The Journal of biological chemistry

|January 26, 2025

概括

在乳腺癌中发现的常见雌激素受体α (ERα) 突变 (Y537S,D538G) 通过稳定螺旋12 (H12) 来促进连接体独立激活. 这种构成性ERα活性有助于癌症的进展和内分泌治疗耐药性.

科学领域:

分子生物学分子生物学
生物化学生物化学
癌症研究癌症研究

背景情况:

在雌激素受体α-LBD (雌激素受体α-LBD) 的体内Y537S和D538G突变与ER-阳性乳腺癌的进展有关.
假设这些突变增加了ERα-LBD灵活性,特别是螺旋体12 (H12),从而导致连接体独立的受体激活.

研究的目的:

研究Y537S和D538G突变对ERα-LBD H12动态的结构影响.
确定这些突变是否会诱导独立于连接体结合的构成性活性ERα构造.

主要方法:

采用了双分四氨酸显示技术.
采用二二基化物 FlAsH-EDT2 来监测H12的结构转变.
分析了具有Y537S或D538G突变的ERα-LBDs,缺少或存在17β-雌激醇.

主要成果:

Y537S和D538G突变促使H12采用稳定的激动体构造,模仿结合体结合的野生型ERα-LBD.
未结合的Y537S和D538G突变ERα-LBD对H12过渡到非活性状态表现出抵抗力.
突变通过直接改变H12动态来赋予构成性ERα活性.

结论:

在ERα-LBD中的Y537S和D538G突变通过稳定H12在激动体构造中导致构成性活性受体.
这些发现阐明了这些突变的ER阳性乳腺癌中增强的增殖,存活和转移的基础分子机制.
这项研究提供了关于ER阳性乳腺癌对内分泌和抗雌激素疗法的耐药性的见解.

关键词:

17β-雌二醇是17β-雌二醇中的一种.酸二的高化物.双部分四半氨酸显示器显示.雌激素受体阿尔法受体是什么螺旋 12 个过渡的过渡.蛋白质动力学蛋白质动力学一类核受体1型核受体

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