Building 3D-structural model of kappa opioid receptor and studying its interaction mechanism with dynorphin A(1-8)~1  

κ阿片受体三维结构的模建及其与强啡肽A(1-8)作用机制的研究(英文)

作　　者：万旭虎[1] 黄小琴[1] 周德和 蒋华良[1] 陈凯先[1] 池志强 

机构地区：[1]中国科学院上海药物研究所,上海中国200031

出　　处：《Acta Pharmacologica Sinica》2000年第8期32-39,共8页中国药理学报（英文版）

摘　　要：To construct the 3D-structural model of human kappa opioid receptor (HKOR) and study its interacting mechanism with dynorphin A( 1 - 8) (Dyn8). METHODS: Comparative molecular modeling was applied to build the 7 transmembrane (TM) helical domain of HKOR using the bovine rhodopsin (OPSD) model as a template. Molecular dynamics was performed to minimize the HKOR model and to simulate the 3D-structure of Dyn8 based on the NMR results of dynorphin A( 1 - 14). The extracellular loops (EL) were built by self-constructed database searching. D0CK4. 0 program was performed to construct Dyn8 complex with HKOR. RESULTS: (1) The model of HKOR was obtained and validated by theoretical and experimental data. (2) The Dyn8-HK0R interacting mechanism is reasonably explained; Side chain of residue Aspl38 interacts with pro-tonated nitrogen atom at the N-terminal residues of Dyn8 through electrostatic and hydrogen bonding, which play an important role in ligand binding with receptor. (3) Negatively charged amino acids in the second extracelluar loop (EL2) as Asp223 and Glu209 interact with the C-terminal positively charged residues in Dyn8, and Glu209 is a likely determinant of peptide ligand specificity. CONCLUSION: Some amino acid residues positioned in EL2, TM3, TM4, and TM5 form the binding site and therefore determine the selectivity of kappa peptide agonist.目的:模建人Kappa阿片受体(HKOR)三维结构,并研究它与强啡肽A(1-8)(Dyn8)的相互作用机制。方法:以牛视紫红质(OPSD)为模板,运用比较分子模拟模建HKOR七段跨膜区的三维结构。运用分子动力学优化HKOR模型并根据强啡肽A(1-14)核磁共振结果构建其三维结构,通过自建数据库搜寻建立HKOR的膜外环区。应用DOCK4.0将强啡肽A(1-8)与HKOR进行对接。结果:(1)得到HKOR三维模型,并用理论及实验参数进行了校正。(2)合理解释了Dyn8-HKOR相互作用机制:Asp138通过与Dyn8的N端残基形成氢键及静电作用,在配体受体结合过程中起着重要的作用。(3)HKOR膜外第二环区(EL2)中带负电荷的氨基酸Asp223和Glu209与Dyn8的C端带正电荷的残基相互作用,而Glu209可能是决定肽类配体特异性的一个重要因素。结论:EL2,TM3,TM4,TM5上的一些关键氨基酸残基决定Kappa阿片受体与肽类配体的选择性结合。

关 键 词：molecular dynamics simulation kappa opioid receptors molecular models binding sites DYNORPHINS 

分 类 号：R96[医药卫生—药理学]