洞察内源性神经类固醇配体与西格玛-1受体的结合情况
Chunting Fu1, Yang Xiao1, Xiaoming Zhou2
1Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Nature communications
|July 4, 2024
概括
结构洞察力揭示了内源性神经类固醇如何与西格玛-1受体 (σ1R) 结合. 尽管在相似的部位结合,但孕激素和脱二三酸盐 (DHEAS) 呈现相反的方向,影响受体活性.
科学领域:
- 结构生物学是结构生物学.
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 西格玛-1受体 (σ1R) 是一种非阿片类受体,与各种生理过程有关.
- 已经确定了σ1R的内源配体,但它们的结合机制仍然不清楚.
研究的目的:
- 阐明内源性神经类固醇与σ1R结合的结构基础.
- 了解孕激素和脱水氨硫酸盐 (DHEAS) 对 σ1R 的独特结合方式.
主要方法:
- 在高分辨率 (2.153.09 Å) 的Xenopus laevis σ1R (xlσ1R) 结晶和结构确定.
- 与内源性神经类固醇共同结晶:孕激素和DHEAS.
- 分子动力学模拟和结合分析.
主要成果:
- 晶体结构显示孕激素和DHEAS结合到xlσ1R中的一个共同位置,主要是通过疏水相互作用.
- 神经类固醇在xlσ1R结合口袋中表现出令人惊的相反的结合方向.
- DHEAS形成直接的键,而孕激素通过水分子间接相互作用,表明不同的功能结果.
结论:
- 这项研究提供了第一个内源性神经类固醇与σ1R结合的结构证据.
- 孕激素和DHEAS的相反的结合方向为它们作为对抗剂和激动剂的不同作用提供了机制性的见解.
- 确定了潜在的水进入途径,有助于理解 σ1R 功能和连接体相互作用.
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