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5-HT3 受体配体识别的结构基础。

Structural basis of ligand recognition in 5-HT3 receptors.

机构信息

Laboratory of Structural Neurobiology, KULeuven, Leuven, Belgium.

出版信息

EMBO Rep. 2013 Jan;14(1):49-56. doi: 10.1038/embor.2012.189. Epub 2012 Nov 30.

DOI:10.1038/embor.2012.189
PMID:23196367
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3537142/
Abstract

The 5-HT(3) receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT(3) receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT(3) receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT(3) receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT(3) receptor.

摘要

5-HT(3) 受体是一种五聚体血清素门控离子通道，介导快速兴奋性神经递质传递，是一类具有重要治疗价值的止吐药物（如格拉司琼）的作用靶点。我们报告了一种与 5-HT(3) 受体亲和力相当的结合蛋白的晶体结构，该蛋白经过工程设计可识别激动剂血清素和拮抗剂格拉司琼。在与血清素结合的结构中，我们观察到与 E 环结合位点残基的亲水相互作用，这可能使通道开放发生转变。在与格拉司琼结合的结构中，我们观察到配体的吲唑部分与 D 环中的阳离子中心之间存在关键的阳离子-π 相互作用，这在 5-HT(3) 受体中是独特存在的。我们使用一系列经过化学修饰的格拉司琼类似物，证明了这种静电相互作用对人 5-HT(3) 受体中高亲和力配体结合的能量贡献。我们的研究首次提供了 5-HT(3) 受体中血清素识别和拮抗剂作用的结构视角。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/5326b70ec8b3/embor2012189f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/89c3e14a9294/embor2012189f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/4b18eb146d1c/embor2012189f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/64ff939dc191/embor2012189f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/5326b70ec8b3/embor2012189f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/89c3e14a9294/embor2012189f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/4b18eb146d1c/embor2012189f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/64ff939dc191/embor2012189f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/943e/3537142/5326b70ec8b3/embor2012189f4.jpg

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