Wan X H, Huang X Q, Zhou D H, Jiang H L, Chen K X, Chi Z Q
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China.
Acta Pharmacol Sin. 2000 Aug;21(8):701-8.
To construct the 3D-structural model of human kappa opioid receptor (HKOR) and study its interacting mechanism with dynorphin A(1-8) (Dyn8).
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. DOCK4.0 program was performed to construct Dyn8 complex with HKOR.
(1) The model of HKOR was obtained and validated by theoretical and experimental data. (2) The Dyn8-HKOR interacting mechanism is reasonably explained: Side chain of residue Asp138 interacts with protonated 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 extracellular 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.
Some amino acid residues positioned in EL2, TM3, TM4, and TM5 form the binding site and therefore determine the selectivity of kappa peptide agonist.
构建人κ阿片受体（HKOR）的三维结构模型，并研究其与强啡肽A（1 - 8）（Dyn8）的相互作用机制。
采用比较分子建模方法，以牛视紫红质（OPSD）模型为模板构建HKOR的7个跨膜（TM）螺旋结构域。基于强啡肽A（1 - 14）的核磁共振结果，进行分子动力学模拟以优化HKOR模型并模拟Dyn8的三维结构。通过自建数据库搜索构建细胞外环（EL）。使用DOCK4.0程序构建Dyn8与HKOR的复合物。
（1）获得了HKOR模型，并通过理论和实验数据进行了验证。（2）合理地解释了Dyn8 - HKOR的相互作用机制：残基Asp138的侧链通过静电和氢键与Dyn8 N端残基的质子化氮原子相互作用，这在配体与受体结合中起重要作用。（3）第二细胞外环（EL2）中的带负电荷氨基酸如Asp223和Glu209与Dyn8 C端带正电荷的残基相互作用，且Glu209可能是肽配体特异性的决定因素。
位于EL2、TM3、TM4和TM5中的一些氨基酸残基形成了结合位点，因此决定了κ肽激动剂的选择性。
