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食欲素受体结合和激活的决定因素——分子动力学研究。

Determinants of Orexin Receptor Binding and Activation-A Molecular Dynamics Study.

机构信息

Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy , University of Helsinki , POB 56, FI-00014 Helsinki , Finland.

Division of Pharmaceutical Biosciences, Faculty of Pharmacy , University of Helsinki , POB 56 , FI-00014 Helsinki , Finland.

出版信息

J Phys Chem B. 2019 Mar 28;123(12):2609-2622. doi: 10.1021/acs.jpcb.8b10220. Epub 2019 Mar 18.

DOI:10.1021/acs.jpcb.8b10220
PMID:30786708
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6727383/
Abstract

We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol-POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.

摘要

我们通过广泛的分子动力学模拟来评估神经肽食欲素-A 在 OX 受体中两种先前提出的结合模式的稳定性。由于受体的激活决定因素仍然未知，我们模拟了一个未配体结合的受体和两种小分子配体，即拮抗剂苏沃雷生和激动剂 Nag26 进行比较。每个系统都在纯 POPC 膜以及 25%胆固醇-POPC 膜中进行了模拟。总共进行了 36 μs 的模拟。通过这组模拟，我们报告了食欲素-A 的 C 末端的稳定结合模式。此外，我们还提出了一些能够促进食欲素受体激活的相互作用，以及一些能够稳定非活性状态的相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbb0/6727383/014f67d75476/jp-2018-102208_0011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbb0/6727383/09feb5c87baf/jp-2018-102208_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbb0/6727383/9fb68d47ff8d/jp-2018-102208_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbb0/6727383/74342586f113/jp-2018-102208_0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbb0/6727383/014f67d75476/jp-2018-102208_0011.jpg

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