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NTSR1的结构动力学和变构效应研究
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Abstract:
神经降压素受体-1 (the neurotensin receptor 1, NTSR1)是一种G蛋白偶联受体(G-protein-coupled receptor, GPCR)，通过响应胞外侧的刺激重排受体的中间层，在胞内侧形成一个容纳效应蛋白的空腔。NTSR1在中枢神经系统、心血管系统、胃肠道消化系统中表现出重要的生物学活性，是关键的药物靶点。基于各向异性网络模型(anisotropic network model, ANM)，本文系统地分析了NTSR1的结构动力学和变构效应。通过计算慢运动和快运动模式下残基的均方涨落及运动相关性，识别出了与受体结构稳定性和信号转导相关的重要残基，揭示了保守基序间的协同关联。微扰响应扫描(perturbation-response scanning, PRS)给出了残基的敏感–效应性矩阵，描述了受体内的变构通讯网络。这项工作有助于深入对NTSR1功能机制的理解，为基于结构的药物设计提供了理论指导。
The neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR). GPCRs rearrange the middle layer of the receptor in response to extracellular stimuli to form a cavity on the intracellular side that accommodates effector proteins. NTSR1 exhibits important biological activities in the central nervous system, cardiovascular system, and gastrointestinal digestive system, being an important drug target. In this work, the structural dynamics and allosteric effects of NTSR1 are systematically analyzed through the anisotropic network model (ANM). The important residues related to structural stability and signal transduction patterns of the receptor are identified by theresidual mean square fluctuation for slow and fast motion modes. Motion correlation analysis reveals positively correlated motions between conserved motifs in class A GPCRs. The sensitivity-response matrix obtained by perturbation-response scanning (PRS) describes the allosteric communication network within the receptor. This work contributes to a deeper understanding of the functional mechanism of NTSR1 and provides theoretical guidance for structure-based drug design.
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