胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究  

Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations

作　　者：曹洪玉[1,2] 金晓军 郭委 余雅娴 史龙飞 唐乾[1,2] 郑学仿[1,2] CAO Hongyu;JIN Xiaojun;GUO Wei;YU Yaxian;SHI Longfei;TANG Qian;ZHENG Xuefang(College of Life Science and Biotechnology;Liaoning Key Laboratory of Bio-Organic Chemistry, Dalian University, Dalian 116622, China;Qilu Pharmaceutical, Jinan 250101, China)

机构地区：[1]大连大学生命科学与技术学院 [2]辽宁省生物有机化学重点实验室,大连116622 [3]齐鲁制药有限公司,济南250101

出　　处：《高等学校化学学报》2018年第5期1026-1033,共8页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:21571025;21601025;21601024);大连市青年科技之星项目(批准号:2016-61)资助~~

摘　　要：采用分子动力学模拟方法研究了胰高血糖素样肽-1(GLP-1)与GLP-1受体(GLP-1R)胞外区域的相互作用.结果表明,配体的结合导致受体的构象发生改变,Loop2区域的氨基酸Pro90和Trp91以及C末端的Glu128向配体移动.根据保守位点突变受体(P73A,V81L,Y88A,P90A和W91A)后所得多肽模拟数据,发现Loop2区域在突变体中的结构和柔性均发生了明显变化,Trp91和Tyr88的突变将导致配体亲和力丧失.研究结果证明,P73A突变型受体和野生型受体分别与配体相互作用后,二者数值差别不大,因此Pro73不是关键残基;V81L突变体则会导致配体亲和力的丧失.该结果为GLP-1药物设计提供了重要理论依据.Binding interactions between the extracellular amino-terminal domain（ ECD） of glucagon-like peptide-1（ GLP-1） receptor and GLP-1 were studied by molecular dynamics simulations. As shown in calculation results,the binding ligand led to conformational changes of the receptor. Pro90 and Trp91 in Loop2 and Glu128 in the C-terminus moved towards the ligand upon ligand binding. The receptor ECD was mutated in some conserved residues（ P73 A,V81 L,Y88 A,P90 A and W91 A）,whose structures and flexibilities have changed violently. Mutations of Trp91 and Tyr88 led to complete loss of binding affinity of the ligand and the effects of those mutations were discussed elaborately. Given all the results,there was no big difference between the interactions related to the receptor ECDP73 Aand the wild type,which suggested that Pro73 was not vital for ligand binding,while mutation of V88 L might make a complete affinity loss of GLP-1.

关 键 词：胰高血糖素样肽-1 保守位点 分子动力学模拟 突变体 

分 类 号：O641[理学—物理化学] Q518[理学—化学]