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.
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.
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通过高斯加速分子动力学（GaMD）模拟深入了解hGPR40的部分激动剂MK-8666和完全变构激动剂AP8之间正协同的分子机制
DOI：
10.1016/j.csbj.2021.07.008
复制
发表时间：
2021
影响因子：
6
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
An X;Bai Q;Bing Z;Liu H;Yao X
通过GaMD模拟揭示了hGPR 40的部分激动剂和AgoPAM结合位点之间的双向诱导拟合构象偶联的机制。人游离脂肪酸受体1（FFAR 1，也称为hGPR 40）的激活以葡萄糖依赖性方式增强胰岛素分泌。因此，开发靶向hGPR 40的选择性激动剂已被提议作为2型糖尿病的治疗策略。一些针对hGPR 40的激动剂被报道。放射性配体结合研究和晶体结构表明GPR 40上存在多个位点，部分激动剂MK-8666和完全变构激动剂（AgoPAM）AP 8之间存在正结合协同效应。在这项工作中，我们进行了长时间的高斯加速分子动力学（GaMD）模拟hGPR 40阐明的两个激动剂之间的协同作用在不同的网站的机制。我们的研究结果表明，诱导适合的构象耦合是双向的两个网站之间。TM 3、TM 4、TM 5和TM 6由于其固有的柔性而产生的运动和旋转在耦合两个激动剂结合位点的构象变化中是至关重要的。这些螺旋在与替代配体或两种配体结合时采用相似的构象状态。Leu1384.57、Leu1865.42和Leu1905.46对两个口袋中残基的重排起协调作用，使两个位点中残基的运动类似齿轮运动。这些结果在原子水平上提供了GPR 40不同位点之间构象偶联的详细信息，也为进一步设计新的GPR 40激动剂提供了结构信息。此外，这些结果表明，在基于结构的配体发现中，考虑其他结合位点的影响是必要的。
The mechanism of bidirectional induced-fit conformational coupling between partial agonist and AgoPAM binding sites of hGPR40 revealed by 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 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.
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DOI：
10.1111/dom.12467
发表时间：
2015-07
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Kaku K;Enya K;Nakaya R;Ohira T;Matsuno R
通讯作者：
Matsuno R
影响因子：
6.7
作者：
Choi, Yun Jung;Shin, Dongyun;Lee, Ju-Yeun
通讯作者：
Lee, Ju-Yeun
影响因子：
3
作者：
Bhattarai, Apurba;Wang, Jinan;Miao, Yinglong
通讯作者：
Miao, Yinglong
影响因子：
4.2
作者：
Christiansen, Elisabeth;Hansen, Steffen V. F.;Urban, Christian;Hudson, Brian D.;Wargent, Edward T.;Grundmann, Manuel;Jenkins, Laura;Zaibi, Mohamed;Stocker, Claire J.;Ullrich, Susanne;Kostenis, Evi;Kassack, Matthias U.;Milligan, Graeme;Cawthorne, Michael A.;Ulven, Trond
通讯作者：
Ulven, Trond
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML