NR2B的同源模建及其与Con-G的对接(英文)

Homology model of NR2B and its binding with Con-G

利用3种同源蛋白结构,通过同源模建的方法构建N-甲基-D-天冬氨酸(NMDA)受体NR2B亚基的三维构象,并对模建蛋白进行多种参数的验证.结果表明:在构建的模型中,conantokin-G(Con-G,NR2B亚基受体拮抗剂)与NR2B对接后,Con-G能很好地嵌入到NR2B亚基激动剂结合部位,并且Con-G的构象基本不变,仍保持α-螺旋构象;Con-G的E2、Gla4、L5、Q9、I12和Q13,NR2B的E420、S421、D423、K458和D715是参与相互作用的重要氨基酸,它们之间形成了一些重要的氢键.该模型的建立对预测NMDA受体与其配体的相互作用具有一定的作用,为设计新的NMDA受体激动剂和拮抗剂提供了重要线索.

A better understanding of the molecular determinants of agonist or antagonist selectivity and efficacy at the NMDA receptor is of both mechanistic and medical interest,and it might facilitate the design of therapeutically applicable compounds.In this work,homology model NR2B subunits of the NMDA receptor was constructed using three structural templates for the model building.This subunit model with the lowest energy was then assessed for the stereochemical quality and side chain environment.Conantokin-G（Con-G） was docked into the model allowing further validation of the active site architecture.In docking studies,the helical conformation of Con-G found in the solution was maintained in the bound state,and its structure was nicely fitted into the agonist binding cleft on the NR2B subunit.Structurally and functionally important residues were identified,including E2,Gla4,L5,Q9,I12 and Q13 of Con-G,and they interacted with E420,S421,D423,K458 and D715 of NR2B.Several H-bonds were also found.This model is consistent with most of the previous experiments,and should be useful for predicting binding interactions of newly designed NMDA receptor ligands.It may provide important clues in the discovery of useful NMDA receptor agonists and antagonists.