人类ABCB1对结合部位访问和连接体识别的结构洞察力
Devanshu Kurre1, Phuoc X Dang1,2, Le T M Le1,3
1The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, United States.
bioRxiv : the preprint server for biology
|August 26, 2024
概括
人类ABCB1排泄结构显示出不同的形状,为药物运输机制和多药物耐药性提供了新的见解. 这些发现对于设计更好的ABCB1抑制剂至关重要.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 结合ATP的磁带亚家族B成员1 (ABCB1) 蛋白质是关键的排泄,参与细胞药物处理和多药物耐药性的发展.
- 在ABCB1的多特异基质识别和传输背后的精确机制仍然不完全理解.
研究的目的:
- 阐明人类ABCB1功能的结构机制,包括基质结合和运输.
- 为了解ABCB1在抗药性中的作用提供高分辨率的结构数据.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定嵌入脂质的人类ABCB1.1的结构.
- 在3.43.9 Å分辨率下,结构在apo,基质结合,抑制剂结合和核酸被困状态中得到解析.
- 避免了稳定抗体和突变,以捕获本地形状.
主要成果:
- 对于ABCB1.1的每个功能状态,都发现了不同的形状.
- 基质结合部位位于不对称的位置,最初被跨膜螺旋4 (TM4) 阻塞.
- 跨膜螺旋布局和连接体结合化学的显著差异区分了基质和抑制剂结合,其中TM4是结构变化的中心.
结论:
- 结构不对称,二次结构断裂和脂质相互作用对ABCB1功能至关重要.
- 这些发现为ABCB1的传输机制提供了基本的见解.
- 这些结果对ABCB1抑制剂的合理设计和基质结合概况的预测具有重要意义.
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