基于各向异性网络模型研究δ阿片受体的动力学与关键残基

Dynamics and Key Residues ofδOpioid Receptor Investigated by Anisotropic Network Model

目的阿片受体是一种G蛋白偶联受体(GPCR),主要通过变构转导胞外区内源性配体结合信号,使其与胞内区效应蛋白偶联来介导镇痛反应。δ阿片受体(DOP)除了与疼痛控制有关外,还与情绪控制有关,是一个很有吸引力的治疗靶点。本文旨在分析DOP的结构动力学和变构效应。方法首先利用各向异性网络模型(anisotropic network model,ANM)对DOP进行建模,通过慢运动模式和快运动模式残基涨落探索DOP的结构动力学与功能的关系。然后,结合微扰响应扫描(perturbation-response scanning,PRS)对DOP中与变构通信相关的关键残基进行识别。结果慢运动模式可以很好地识别DOP的结构以及功能性钠离子结合位点,快运动模式可以识别出对蛋白质结构稳定起重要作用的关键残基。残基运动相关性分析发现胞外/胞内的跨膜螺旋与环状区域之间存在正相关性,这些区域相互作用促进DOP与配体的结合。PRS分析中敏感性高和效应性高的关键残基在DOP的变构通信中发挥重要作用。结论这项工作有助于加强对δ阿片受体变构通讯机制的理解,并为药物设计提供有价值的信息。

Objective Opioid receptor,a kind of G protein-coupled receptors(GPCRs),mainly mediates an analgesic response via allosterically transducing the signal of endogenous ligand binding in the extracellular domain to couple to effector proteins in the intracellular domain.δopioid receptor(DOP)is associated with emotional control besides pain control,which makes it an attractive therapeutic target.However,its allosteric mechanism and key residues responsible for structural stability and signal transmission are not completely clear.This paper aims to analyze the structural dynamics and allosteric effects of DOP.Methods Firstly,the relationships between DOP structure dynamics and function were explored by means of residue fluctuations in slow motion mode and fast motion mode from the anisotropic network model(ANM).Then,perturbation response scanning(PRS)was used to identify key residues related to allosteric communication in DOP.Results The DOP segments and functional sodium-binding sites can be well identified by the slowest motion modes,and the key residues that play a crucial role in protein structural stability can be identified by the fastest motion modes.Correlation analysis of residue motions reveals positive correlations between extracellular/intracellular transmembrane helices and loops,which promote the DOP structural stability and the binding of DOP with ligands.Key residues with high sensitivity and high effectiveness in PRS analysis play an important role in the allosteric communication of DOP.Conclusion This work sheds light on the allosteric communication mechanism ofδopioid receptor and provides valuable information for drug design.