Liu D X, Jiang H L, Shen J S, Zhu W L, Zhao L, Chen K X, Ji R Y
Shanghai Institutes of Materia Medica, Chinese Academy of Sciences, China.
Zhongguo Yao Li Xue Bao. 1999 Feb;20(2):131-6.
To study the interaction between kappa-opioid receptor and its nonpeptide agonists.
The "conservation patterns" for G-protein coupled receptors (GPCR) were used to determine 7 transmembrane (TM) regions. Taking the crystallographic coordinates of bacteriorhodopsin (BR) as the template, the 3D structural model was constructed for 7 TM of kappa-opioid subtype with molecular mechanics (MM) method. Five highly active nonpeptide kappa-opioid agonists were docked into the 7 helices of kappa-opioid receptor to study the ligand-receptor interaction.
Four important interactions between U-50488-like agonists and kappa-opioid receptors were drawn according to our modeling study: (1) the protonated pyrrolidine nitrogen of the ligands formed a hydrogen-bond with the carboxyl of Asp138; (2) the carbonyl oxygen of ligands forms a hydrogen bond to the hydroxyl of Ser187; (3) the aryl groups connected to acylamide of the agonists inserted into a hydrophobic cavity enclosed by residues Val239, Val236, Phe235, Val232, Leu186, and Trp183; (4) the pyrrolidine of the ligands in the complexes was surrounded by Ile290, Asp138, Ile194, Ile135, and Cys131.
The proposed interaction mechanism is helpful for further mutant experiments and designing novel potent kappa-opioid agonists.
研究κ-阿片受体与其非肽类激动剂之间的相互作用。
利用G蛋白偶联受体（GPCR）的“保守模式”确定7个跨膜（TM）区域。以细菌视紫红质（BR）的晶体学坐标为模板，采用分子力学（MM）方法构建κ-阿片亚型7个TM的三维结构模型。将5种高活性非肽κ-阿片激动剂对接至κ-阿片受体的7个螺旋中，以研究配体-受体相互作用。
根据我们的建模研究，得出U-50488样激动剂与κ-阿片受体之间的4种重要相互作用：（1）配体的质子化吡咯烷氮与Asp138的羧基形成氢键；（2）配体的羰基氧与Ser187的羟基形成氢键；（3）与激动剂酰胺基相连的芳基插入由Val239、Val236、Phe235、Val232、Leu186和Trp183残基围成的疏水腔中；（4）复合物中配体的吡咯烷被Ile290、Asp138、Ile194、Ile135和Cys131环绕。
所提出的相互作用机制有助于进一步开展突变实验和设计新型强效κ-阿片激动剂。
