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

doi:10.1021/acschemneuro.9b00630

	Revealing the Positive Binding Cooperativity Mechanism between the Orthosteric and the Allosteric Antagonists of CCR2 by Metadynamics and Gaussian Accelerated Molecular Dynamics Simulations
	An, Xiaoli 2,3; Bai, Qifeng 5; Bing, Zhitong 5,6; Liu, Hongli 1; Zhang, Qianqian 1; Liu, Huanxiang 1; Yao, Xiaojun 2,3,4
刊名	ACS CHEMICAL NEUROSCIENCE
	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
DOI	10.1021/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.
资助项目	National Natural Science Foundation of China[2175060]
WOS关键词	TRANSMEMBRANE PROLINES ; RECEPTOR ANTAGONISTS ; CHEMOKINE RECEPTORS ; FUNCTIONAL-ROLE ; WEB SERVER ; PROTEIN ; ACTIVATION ; RESIDUES ; SITE ; CONSTRAINTS
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000515195800013
资助机构	National Natural Science Foundation of China
内容类型	期刊论文
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.