Molecular modeling on kappa opioid receptor and its interaction with nonpeptide kappa opioid agonists

Molecular modeling on kappa opioid receptor and its interaction with nonpeptide kappa opioid agonists 1

目的：研究κ阿片受体及其与非肽类激动剂的作用机制．方法：以细菌视紫红质为模板，模建κ阿片受体七个跨膜区的三维结构；将五个高活性非肽类激动剂对接到螺旋区内，研究作用机制．结果：（１）四氢吡咯环氮原子与Ａｓｐ１３８羧基成氢键；（２）乙酰胺羰基氧与受体Ｓｅｒ１８７间存在氢键作用；（３）与乙酰胺相连的疏水基团处于由Ｖａｌ２３９、Ｖａｌ２３６、Ｐｈｅ２３５、Ｖａｌ２３２、Ｌｅｕ１８６和Ｔｒｐ１８３构成的疏水区域内；（４）激动剂的四氢吡咯环为Ｉｌｅ２９０、Ａｓｐ１３８、Ｉｌｅ１９４、Ｉｌｅ１３５和Ｃｙｓ１３１残基包围．结论：模型将有助于设计新型高效安全的κ阿片受体激动剂．

AIM: To study the interaction between κ opioid receptor and its nonpeptide agonists. METHODS: The “conservation patterns” for G protein coupled receptors (GPCR) were used to determine 7 transmembrane (TM) regions. Taking the crystallographic coordinates of bacterior￣hodopsin (BR) as the template, the 3D structural model was constructed for 7 TM of κ opioid subtype with molecular mechanics (MM) method. Five highly active nonpeptide κ opioid agonists were docked into the 7 helices of κ opioid receptor to study the ligand receptor interaction. RESULTS: Four important inter￣actions between U 50488 like agonists and κ 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. CONCLUSION: The proposed interaction mechanism is helpful for further mutant experiments and designing novel potent κ opioid agonists.