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
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 we...
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doaj-ef14d48b7d164e7396149f781c96a9292021-07-19T04:09:48ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011939783989Insights 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) simulationsXiaoli An0Qifeng Bai1Zhitong Bing2Huanxiang Liu3Xiaojun Yao4State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, ChinaSchool of Basic Medical Science, Lanzhou University, Lanzhou, ChinaInstitute of Modern Physics of Chinese Academy of Sciences, Gansu Province, Lanzhou, ChinaSchool of Pharmacy, Lanzhou University, Lanzhou 730000, China; Corresponding authors State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China (X. Yao).State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China; Corresponding authors State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China (X. Yao).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 Leu1384.57, Leu1865.42 and Leu1905.46 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.http://www.sciencedirect.com/science/article/pii/S2001037021002981hGPR40Positive binding cooperativityPartial agonistAgoPAMGaussian accelerated molecular dynamics simulation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaoli An Qifeng Bai Zhitong Bing Huanxiang Liu Xiaojun Yao |
spellingShingle |
Xiaoli An Qifeng Bai Zhitong Bing Huanxiang Liu Xiaojun Yao 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 hGPR40 Positive binding cooperativity Partial agonist AgoPAM Gaussian accelerated molecular dynamics simulation |
author_facet |
Xiaoli An Qifeng Bai Zhitong Bing Huanxiang Liu Xiaojun Yao |
author_sort |
Xiaoli An |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Elsevier |
series |
Computational and Structural Biotechnology Journal |
issn |
2001-0370 |
publishDate |
2021-01-01 |
description |
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 Leu1384.57, Leu1865.42 and Leu1905.46 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. |
topic |
hGPR40 Positive binding cooperativity Partial agonist AgoPAM Gaussian accelerated molecular dynamics simulation |
url |
http://www.sciencedirect.com/science/article/pii/S2001037021002981 |
work_keys_str_mv |
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