Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations

doi:10.1016/j.csbj.2021.07.008

	Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations
	An, Xiaoli 2,4; Bai, Qifeng 3; Bing, Zhitong 6; Liu, Huanxiang 1; Yao, Xiaojun 2,4,5
刊名	COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
	2021
卷号	19 页码:3978-3989
关键词	hGPR40 Positive binding cooperativity Partial agonist AgoPAM Gaussian accelerated molecular dynamics simulation
ISSN号	2001-0370
DOI	10.1016/j.csbj.2021.07.008
通讯作者	Liu, Huanxiang(hxliu@lzu.edu.cn) ; Yao, Xiaojun(xjyao@lzu.edu.cn)
英文摘要	Activation of human free fatty acid receptor 1 (FFAR1, also called hGPR40) enhances insulin secretion in a glucose-dependent manner. Hence, the development of selective agonist targeting hGPR40 has been proposed as a therapeutic strategy of type 2 diabetes mellitus. Some agonists targeting hGPR40 were reported. The radioligand-binding studies and the crystal structures reveal that there are multiple sites on GPR40, and there exists positive binding cooperativity between the partial agonist MK-8666 and full allosteric agonist (AgoPAM) AP8. In this work, we carried out long-time Gaussian accelerated molecular dynamics (GaMD) simulations on hGPR40 to shed light on the mechanism of the cooperativity between the two agonists at different sites. Our results reveal that the induced-fit conformational coupling is bidirectional between the two sites. The movements and rotations of TM3, TM4, TM5 and TM6 due to their inherent flexibility are crucial in coupling the conformational changes of the two agonists binding sites. These helices adopt similar conformational states upon alternative ligand or both ligands binding. The Leu138(4.57), Leu186(5.42) and Leu190(5.46) play roles in coordinating the rearrangements of residues in the two pockets, which makes the movements of residues in the two sites like gear movements. These results provide detailed information at the atomic level about the conformational coupling between different sites of GPR40, and also provide the structural information for further design of new agonists of GPR40. In addition, these results suggest that it is necessary by considering the effect of other site bound in structure-based ligands discovery. (C) 2021 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
资助项目	National Natural Science Foundation of China[21775060]
WOS关键词	FATTY-ACID RECEPTOR ; PANCREATIC BETA-CELLS ; 1 FFA1/GPR40 AGONIST ; INSULIN-SECRETION ; TRANSMEMBRANE PROLINES ; FASIGLIFAM TAK-875 ; FUNCTIONAL-ROLE ; GPR40 AGONIST ; DOUBLE-BLIND ; PROTEIN
WOS研究方向	Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000684852400002
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/113462/136617]
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, Sch Basic Med Sci, Lanzhou, Peoples R China 4.Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China 5.Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau Inst Appl Res Med & Hlth, Taipa, Macau, 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. Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations[J]. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL,2021,19:3978-3989.
APA	An, Xiaoli,Bai, Qifeng,Bing, Zhitong,Liu, Huanxiang,&Yao, Xiaojun.(2021).Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations.COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL,19,3978-3989.
MLA	An, Xiaoli,et al."Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations".COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL 19(2021):3978-3989.