洞察到Mena的EVH1领域的交互景观
Lanette LaComb1, Agnidipta Ghosh1, Jeffrey B Bonanno1
1Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States.
启用/VASP同质性1 (EVH1) 域在疏水裂中结合了富含林的配体. 围绕这些片段的残留物增强了结合亲和力,合成抑制剂的相互作用比天然配体更强.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 启用/VASP同质性1 (EVH1) 域是一个蛋白质模块,与富含林的序列相互作用,对于信号和支架至关重要.
- 含有EVH1的蛋白质Mena在活性动力学,膜贩运和癌症转移中发挥作用.
研究的目的:
- 研究Mena EVH1域与其生理连接体和合成抑制剂的结合特性.
- 通过EVH1域识别特定的氨基酸和参与联结体识别的区域.
主要方法:
- 二维1H-15NHSQCNNMR光谱法用于映射连接体结合位点.
- 内在稳定状态光和光极化试验用于量化结合亲缘关系.
- 高分辨率晶体结构的分析.
主要成果:
- 富含林的配体段与EVH1域的保护的疏水裂结合.
- 沿着富含proline的区域的残留物显著增强了连结体亲和力.
- 一种合成抑制剂 (6c) 与同一个裂口的天然配体 (Kd = 3-8 μM) 相比,具有更高的亲和力 (Kd ≈ 0.3 μM) 结合.
结论:
- 在EVH1域中,除了富含proline的基因外,还利用了侧面残留物来增强连接键的作用.
- 合成分子可以被设计为与自然基质相比,与EVH1域实现更高的亲和力相互作用,提供潜在的治疗策略.
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