Exploring Activation Mechanism Induced by Glutamate for one Homodimer of Class C GPCRs via Molecular Dynamics Simulation
作者单位：College of Chemistry Sichuan University 四川大学
会议名称：《2019中国化学会第十五届全国计算（机）化学学术会议》
会议日期：2019年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
关 键 词：Metabotropic glutamate receptor 1 dimer ligand activation mechanism molecular dynamics simulation protein structure network
摘 要：Metabotropic glutamate receptors of class C GPCRs exist as constitutive dimers, which play important roles in activating excitatory synapses of the central nerve system. However, due to lack of crystal structures and complicated cell environment, the activation mechanism induced by agonists has not been clarified on experiments. To address the problem, we used microsecond allatom molecular dynamics（MD） simulation couple with protein structure network（PSN） to explore the glutamate-induced activation for the mGluR1 homodimer. The results indicate that the glutamate binding stabilizes not only the closure of venus flytrap domains but also the polar interaction of LB2-LB2, in turn keeping the extracelluar domain in the active state. The activation of the excelluar domain drives TMDs closer and induces aymmetric activation for the TMD domains of the two protomers. One protomer with lower binding energy between the agonist and its extracelluar is activated while the other one with higher binding energy is still in the inactive state. The asymmetric ligand-binding and TMD activation between the two protomers should be common features for the GPCR homodimers, either the class A or the class C. PSN identify the allostrical regulation pathway from the ligand-binding pocket in the extracellur domain to the G-protein binding site in the intracellur TMD region, and further reveals that the combination of trans-activation and cisactivation triggers one protomer to be activated. These observations could provide valuable molecular information for understanding of the structure and the implication in drug efficacy for the class C GPCR dimers.