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Revealing the Positive Binding Cooperativity Mechanism between the Orthosteric and the Allosteric Antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations

文献类型：期刊论文

作者An, Xiaoli2,3; Bai, Qifeng5; Bing, Zhitong5,6; Liu, Hongli1; Zhang, Qianqian1; Liu, Huanxiang1; Yao, Xiaojun2,3,4
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2020-02-19
卷号11期号:4页码:628-637
关键词CC chemokine receptor 2 orthosteric antagonist allosteric antagonist binding cooperativity metadynamics simulation Gaussian accelerated MD simulation
ISSN号1948-7193
DOI10.1021/acschemneuro.9b00630
通讯作者Liu, Huanxiang(hxliu@lzu.edu.cn) ; Yao, Xiaojun(xjyao@lzu.edu.cn)
英文摘要CC chemokine receptor 2 (CCR2) and its endogenous CC chemokine ligands are associated with numerous inflammatory, neurodegenerative diseases, and cancer. CCR2 is becoming an attractive target in the treatment of autoimmune disease and neurodegenerative diseases. The orthosteric antagonist BMS-681 and allosteric antagonist CCR2-RA-[R] of CCR2 show positive binding cooperativity. We performed well-tempered metadynamics simulations and Gaussian accelerated MD simulations to reveal the influence of the orthosteric antagonist on the unbinding of allosteric antagonist of CCR2. We revealed different unbinding pathways of CCR2-RA-[R] in binary complex CCR2-VT5 and ternary complex CCR2-73R-VTS. The different unbinding pathways of CCR2-RA-[R] are due to the conformational dynamics of TM6. We obtained the significant conformational differences of the intracellular side of TM6 upon CCR2 binding to different ligands by GaMD simulation. The conformational dynamics of TM6 are consistent with the unbinding pathway analysis. GaMD simulations indicate that BMS-681 binding restricts the bend of intracellular side of TM6 by stabilizing the extracellular sides of TM6 and TM7. The charged residues Arg206(5.)(43) of TM5 and Glu291(7.)(39) of TM7 play key roles in stabling TM7 and TM6. TM6 and TM7 are crucial components in the orthosteric and allosteric binding sites. Our results illustrate the conformational details about the effect of the orthosteric antagonist on the allosteric antagonist of CCR2. The conformational dynamics of CCR2 upon binding to different ligands can provide a rational basis for development of allosteric ligands of CCR2.
WOS关键词TRANSMEMBRANE PROLINES ; RECEPTOR ANTAGONISTS ; CHEMOKINE RECEPTORS ; FUNCTIONAL-ROLE ; WEB SERVER ; PROTEIN ; ACTIVATION ; RESIDUES ; SITE ; CONSTRAINTS
资助项目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:000515195800013
出版者AMER CHEMICAL SOC
资助机构National Natural Science Foundation of China
源URL[http://119.78.100.186/handle/113462/141093]  
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 Pharm, Lanzhou 730000, Peoples R China
2.Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China
3.Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China
4.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Taipa, Macao, Peoples R China
5.Lanzhou Univ, Sch Basic Med Sci, Lanzhou 730000, Peoples R China
6.Chinese Acad Sci, Inst Modern Phys, Lanzhou, Gansu, Peoples R China
推荐引用方式
GB/T 7714		 An, Xiaoli,Bai, Qifeng,Bing, Zhitong,et al. Revealing the Positive Binding Cooperativity Mechanism between the Orthosteric and the Allosteric Antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations[J]. ACS CHEMICAL NEUROSCIENCE,2020,11(4):628-637.
APA An, Xiaoli.,Bai, Qifeng.,Bing, Zhitong.,Liu, Hongli.,Zhang, Qianqian.,...&Yao, Xiaojun.(2020).Revealing the Positive Binding Cooperativity Mechanism between the Orthosteric and the Allosteric Antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations.ACS CHEMICAL NEUROSCIENCE,11(4),628-637.
MLA An, Xiaoli,et al."Revealing the Positive Binding Cooperativity Mechanism between the Orthosteric and the Allosteric Antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations".ACS CHEMICAL NEUROSCIENCE 11.4(2020):628-637.

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来源：近代物理研究所

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