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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (20): 2271-2278. 上一篇    下一篇

研究论文

神经介素B受体与拮抗剂、激动剂的分子模拟研究

金 莲a 刘 鑫a 王 锐a,b 董守良*,a

  

  1. (a兰州大学 生命科学学院生物化学与分子生物学研究所 兰州 730000)
    (b兰州大学 功能有机分子化学国家重点实验室 兰州 730000)

  • 投稿日期:2008-03-18 修回日期:2008-05-17 发布日期:2008-10-28
  • 通讯作者: 董守良

Molecular Modeling Study on Neuromedin B Receptor with Agonist and Antagonist

JIN, Lian a LIU, Xin a WANG, Rui a,b DONG, Shou-Liang *,a   

  1. (a Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou 730000)
    (b State Key Laboratory and Applied Organic Chemistry, Lanzhou University, Lanzhou 730000)
  • Received:2008-03-18 Revised:2008-05-17 Published:2008-10-28
  • Contact: DONG, Shou-Liang

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大鼠神经介素B受体(rat neuromedin B receptor, rNMBR)属于G蛋白偶联受体(G-protein coupled receptor, GPCR) A家族的成员. GPCR的结构特征和在信号传导中的重要作用决定了其可以作为很好的药物靶标. 关于rNMBR与内源性激动剂神经介素B (neuromedin B, NMB)以及与非肽类拮抗剂pd168368作用机制的研究对于合理设计受体药物分子有重要的指导意义. 在这一研究中, 我们使用同源模建, 构建受体的三维结构, 进行分子对接和分子动力学的计算. 基于受体三维结构, 通过10 ns的空载受体、激动剂-受体、拮抗剂-受体的分子动力学模拟, 探讨受体与激动剂与拮抗剂的作用机制. 研究表明rNMB-R中跨膜(transmembrane, TM)螺旋3, 5, 6, 7参与配体的结合. NMB与受体的结合, 使受体转变为活性构象, 而受体同拮抗剂pd168368恰好相反.

关键词: 神经介素B受体, G-蛋白偶联受体, 同源模建, 分子动力学模拟, 分子对接

Rat neuromedin B receptor (rNMBR) belongs to the family A of G-protein coupled receptor (GPCR). The unique structure and important role in the signaling transduction of GPCR make them very useful for drug targets. So understanding the regulation mechanisms of rNMBR by its agonists and antagonists at the atomic level is essential for reasonably designing rNMBR antagonists as drug candidates for treating NMB-mediated diseases. A 3D model of rNMBR was constructed by homology modeling, and then molecular docking and molecular dynamics (MD) simulations were carried out. Based on the 3D structure, regulation mechanisms of rNMBR by agonists and antagonists were investigated via three 10 ns MD simulations on the systems of apo-rNMBR, rNMBR-NMB and rNMBR-pd168368. It was found that the ligand was located within the transmembrane regions 3, 5, 6, 7 (TM3, TM5, TM6, TM7) of rNMBR, NMB leading the receptor to its activated state. In contrast, binding of pd168368 to rNMBR locked rNMBR in its inactive state.

Key words: neuromedin B receptor, G-protein coupled receptor, homology modeling, molecular dynamics simulation, molecular docking