TRPV1香草口袋内脂肪酰基脂质介质的结合相互作用:分子动力学研究

IF 2.5 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nada Birkic , David Visentin , Željko Svedružić , Christian A. Reynolds
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引用次数: 0

摘要

瞬时受体电位香草素1(TRPV1)通道是一种配体门控的非选择性阳离子通道,在初级感觉神经元中表达,在伤害感受中发挥作用。该通道被湿热、pH、辣椒素和其他内源性香草素激活,包括由多不饱和脂肪酸(PUFA)酶促衍生的脂质介质(LMs)。尽管辣椒素与TRPV1的结合已得到很好的表征,但内源性LM配体结合通道的分子机制尚不清楚。在本研究中,我们使用分子动力学(MD)方法表征了TRPV1香草口袋内13个内源性LM配体的结合相互作用。我们观察到LM配体可以根据它们的结构和对香草口袋的亲和力进行分组。此外,LM配体上极性基团的位置和数量通过与蛋白质的各种极性相互作用直接影响结合稳定性。作为额外的对照,我们对PUFA前体分子亚油酸和花生四烯酸进行了对接实验,它们未能在香草口袋内形成稳定的相互作用。虽然具有相似结构的LM配体显示出相似的结合相互作用,但在20-HETE、9-HODE和9,10-DiHOME的情况下有显著的例外。我们的研究为内源性LM配体激活TRPV1的机制提供了新的见解。观察到的结合相互作用可能有助于解释体内和体外药效学研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Binding interactions of fatty acyl lipid mediators within the vanilloid pocket of TRPV1: A molecular dynamics study

The transient receptor potential vanilloid 1 (TRPV1) channel is a ligand-gated, nonselective cation channel expressed in primary sensory neurons, which has a role in nociception. The channel is activated by noxious heat, pH, capsaicin and other endogenous vanilloids, including lipid mediators (LMs) enzymatically derived from polyunsaturated fatty acids (PUFA). Although capsaicin binding to TRPV1 has been well characterized, the molecular mechanism by which endogenous LM ligands bind the channel is not well understood. In this study, we characterized the binding interactions for 13 endogenous LM ligands, within the vanilloid pocket of TRPV1 using a molecular dynamics (MD) approach. We observed that LM ligands can be grouped based on their structure and affinity for the vanilloid pocket. Furthermore, the position as well as the number of the polar groups on the LM ligand directly impact binding stability through various polar interactions with the protein. As an additional control we performed docking experiments of the PUFA precursor molecules linoleic acid and arachidonic acid which failed to form stable interactions within the vanilloid pocket. While LM ligands with similar structures displayed similar binding interactions, there were notable exceptions in the case of 20-HETE, 9-HODE, and 9,10-DiHOME. Our study offers new insights into the mechanisms involved in TRPV1 activation by endogenous LM ligands. The observed binding interactions may assist in the interpretation of in vivo and in vitro pharmacodynamics studies.

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来源期刊
Prostaglandins & other lipid mediators
Prostaglandins & other lipid mediators 生物-生化与分子生物学
CiteScore
5.80
自引率
3.40%
发文量
49
审稿时长
2 months
期刊介绍: Prostaglandins & Other Lipid Mediators is the original and foremost journal dealing with prostaglandins and related lipid mediator substances. It includes basic and clinical studies related to the pharmacology, physiology, pathology and biochemistry of lipid mediators. Prostaglandins & Other Lipid Mediators invites reports of original research, mini-reviews, reviews, and methods articles in the basic and clinical aspects of all areas of lipid mediator research: cell biology, developmental biology, genetics, molecular biology, chemistry, biochemistry, physiology, pharmacology, endocrinology, biology, the medical sciences, and epidemiology. Prostaglandins & Other Lipid Mediators also accepts proposals for special issue topics. The Editors will make every effort to advise authors of the decision on the submitted manuscript within 3-4 weeks of receipt.
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