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一个与LSD结合的人类血清素受体的晶体结构

Daniel Wacker¹, Sheng Wang¹, John D McCorvy¹

¹Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.

|January 28, 2017

概括

这项研究揭示了LSD与5-HT2B受体的结晶结构,解释了其独特的结合和缓慢的解离. 一个涉及细胞外环盖的分子机制被确定为LSD

科学领域:

结构生物学
神经药理学
生物化学

背景情况:

利瑟基酸二甲胺 (LSD) 是一种强烈的幻觉剂,主要作用于血清素受体.
了解LSD与目标之间的分子相互作用对于阐明其精神活性作用至关重要.

研究的目的:

确定LSD与人类5-HT2B受体 (5-HT2BR) 的结晶结构.
阐明LSD的结合动力学,立体化学和信号的结构基础.
提供LSD对人类血清素受体作用的分子解释.

主要方法:

进行X射线晶体学以获得LSD-5-HT2BR复合结构.
分子动力学 (MD) 模拟以调查结合动力学和机制.
检测细胞外循环2 (EL2) 的作用.

主要成果:

晶体结构显示了5-HT2BR适应LSD的形状重组,解释了其乙胺部分的选择性.
这种药物从5-HT2BR和精神活性目标5-HT2AR中异常缓慢地解离.
MD模拟和突变发生表明EL2形成的盖状结构有助于减缓结合动力学并影响信号偏差.

结论:

这项研究展示了LSD与5-HT2BR相互作用的意想不到结合方式.
在分子层面揭示了LSD的动力学,立体化学和信号的关键特征.
这些发现为LSD对人体血清素受体的影响提供了结构和机制的基础.

关键词:

一个GPCR 结晶学幻觉剂血清素受体结构功能

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