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How Does Agonist and Antagonist Binding Lead to Different Conformational Ensemble Equilibria of the kappa-Opioid Receptor: Insight from Long-Time Gaussian Accelerated Molecular Dynamics Simulation

文献类型：期刊论文

作者An, Xiaoli5,6; Bai, Qifeng1; Bing, Zhitong1,2; Zhou, Shuangyan3,5,6; Shi, Danfeng5,6; Liu, Huanxiang3; Yao, Xiaojun4,5,6
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2019-03-01
卷号10期号:3页码:1575-1584
关键词kappa-opioid receptor Gaussian accelerated molecular dynamics simulation agonist antagonist conformational change
ISSN号1948-7193
DOI10.1021/acschemneuro.8b00535
通讯作者Liu, Huanxiang(hxliu@lzu.edu.cn) ; Yao, Xiaojun(xjyao@lzu.edu.cn)
英文摘要The opioid receptors belong to the class A seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). The kappa-opioid receptor (KOR) is a subfamily of four opioid receptors. The endogenous peptide and a variety of selective agonists and antagonists of KOR have been developed. The structurally similar ligands at the same site cause completely opposite biological functions and induce different conformational changes. To shed light on the conformation ensembles and conformational dynamics in activation and deactivation processes of KOR, we performed all-atom, long-time Gaussian accelerated molecular dynamics simulation (GaMD) on KOR binding with agonist epoxymorphinan MP1104 and antagonist JDTic, respectively. Our results revealed different conformation ensembles of KOR binding with agonist and with antagonist. Agonist binding stabilizes the active state of key motifs including DYYNM motif and CWxP motif, and biases the conformation equilibria toward the active state. Antagonist binding will not destroy inactive conformation equilibria, by keeping the stable inactive state of these crucial motifs. We found that the inactive apo form of KOR is the most stable state, while the active apo form relaxes readily to inactive state. Our results also revealed a stable intermediate (I), which is attributed to the hydrophobic interactions between Tyr246(5.58) and TM6, as well as the steric hindrance of them. Our results not only show the conformation equilibria bias of KOR by binding with agonist and antagonist, but also provide the structural information for the design and discovery of potential ligands with different functions.
WOS关键词PROTEIN-COUPLED RECEPTOR ; STRUCTURAL BASIS ; FUNCTIONAL SELECTIVITY ; ACTIVE STATE ; ACTIVATION ; IDENTIFICATION ; PARAMETERS ; DATABASE ; PATHWAYS ; LIGANDS
资助项目National Natural Science Foundation of China[21475054] ; National Natural Science Foundation of China[2175060]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种英语
WOS记录号WOS:000462259900063
出版者AMER CHEMICAL SOC
资助机构National Natural Science Foundation of China
源URL[http://119.78.100.186/handle/113462/134052]  
专题中国科学院近代物理研究所
通讯作者Liu, Huanxiang; Yao, Xiaojun
作者单位1.Lanzhou Univ, Sch Basic Med Sci, Lanzhou 730000, Gansu, Peoples R China
2.Chinese Acad Sci, Inst Modern Phys, Lanzhou 730000, Gansu, Peoples R China
3.Lanzhou Univ, Sch Pharm, Lanzhou 730000, Gansu, Peoples R China
4.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Taipa, Macau, Peoples R China
5.Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Gansu, Peoples R China
6.Lanzhou Univ, Dept Chem, Lanzhou 730000, Gansu, Peoples R China
推荐引用方式
GB/T 7714		 An, Xiaoli,Bai, Qifeng,Bing, Zhitong,et al. How Does Agonist and Antagonist Binding Lead to Different Conformational Ensemble Equilibria of the kappa-Opioid Receptor: Insight from Long-Time Gaussian Accelerated Molecular Dynamics Simulation[J]. ACS CHEMICAL NEUROSCIENCE,2019,10(3):1575-1584.
APA An, Xiaoli.,Bai, Qifeng.,Bing, Zhitong.,Zhou, Shuangyan.,Shi, Danfeng.,...&Yao, Xiaojun.(2019).How Does Agonist and Antagonist Binding Lead to Different Conformational Ensemble Equilibria of the kappa-Opioid Receptor: Insight from Long-Time Gaussian Accelerated Molecular Dynamics Simulation.ACS CHEMICAL NEUROSCIENCE,10(3),1575-1584.
MLA An, Xiaoli,et al."How Does Agonist and Antagonist Binding Lead to Different Conformational Ensemble Equilibria of the kappa-Opioid Receptor: Insight from Long-Time Gaussian Accelerated Molecular Dynamics Simulation".ACS CHEMICAL NEUROSCIENCE 10.3(2019):1575-1584.

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来源：近代物理研究所

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