激活相关微开关介导的 β2AR 二聚体动力学早期事件

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Aneesh Kotipalli, Shruti Koulgi, Vinod Jani, Uddhavesh Sonavane, Rajendra Joshi
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引用次数: 0

摘要

G 蛋白偶联受体(GPCR)约占人类基因组的 3-4%,是美国食品药物管理局批准的三分之一药物的靶点。GPCR 通常以单体形式存在,但也会聚集形成高阶寡聚体,包括二聚体。β2AR是一种药理相关的GPCR,已知是治疗哮喘和心血管疾病的靶点。人们对β2AR在二聚体水平上的激活仍缺乏深入研究。在本研究中,我们进行了分子动力学(MD)模拟,以了解β2AR在二聚体水平上与活化相关的结构变化。通过对 PDB ID: 2RH1 和 PDB ID:3P0G 的β2AR 二聚体。共进行了约 21μs 模拟。基于残基的距离、RMSD 和 PCA 计算表明,对于无活性和激动剂结合的 β2AR 二聚体,其中任何一个单体都具有与活化相关的特征。在所有模拟中都观察到两个单体中的 TM5 和 TM6 螺旋有显著变化。TM5 凸起以及 TM2 和 TM7 螺旋的接近可能是活化的早期事件之一。据观察,TM1 和螺旋 8 之间的二聚体界面在 Apo 和激动剂结合模拟中保持良好。反向激动剂的存在有利于两种单体的非活性特征。这些已知的单体激活的关键特征被观察到对β2AR二聚体产生了影响,从而使人们对 GPCR 的寡聚机制有了更深入的了解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Early Events in β<sub>2</sub>AR Dimer Dynamics Mediated by Activation-Related Microswitches.

Early Events in β2AR Dimer Dynamics Mediated by Activation-Related Microswitches.

G-Protein-Coupled Receptors (GPCRs) make up around 3-4% of the human genome and are the targets of one-third of FDA-approved drugs. GPCRs typically exist as monomers but also aggregate to form higher-order oligomers, including dimers. β2AR, a pharmacologically relevant GPCR, is known to be targeted for the treatment of asthma and cardiovascular diseases. The activation of β2AR at the dimer level remains under-explored. In the current study, molecular dynamics (MD) simulations have been performed to understand activation-related structural changes in β2AR at the dimer level. The transition from inactive to active and vice versa has been studied by starting the simulations in the apo, agonist-bound, and inverse agonist-bound β2AR dimers for PDB ID: 2RH1 and PDB ID: 3P0G, respectively. A cumulative total of around 21-μs simulations were performed. Residue-based distances, RMSD, and PCA calculations suggested that either of the one monomer attained activation-related features for the apo and agonist-bound β2AR dimers. The TM5 and TM6 helices within the two monomers were observed to be in significant variation in all the simulations. TM5 bulge and proximity of TM2 and TM7 helices may be contributing to one of the early events in activation. The dimeric interface between TM1 and helix 8 were observed to be well maintained in the apo and agonist-bound simulations. The presence of inverse agonists favored inactive features in both the monomers. These key features of activation known for monomers were observed to have an impact on β2AR dimers, thereby providing an insight into the oligomerization mechanism of GPCRs.

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来源期刊
Journal of Membrane Biology
Journal of Membrane Biology 生物-生化与分子生物学
CiteScore
4.80
自引率
4.20%
发文量
63
审稿时长
6-12 weeks
期刊介绍: The Journal of Membrane Biology is dedicated to publishing high-quality science related to membrane biology, biochemistry and biophysics. In particular, we welcome work that uses modern experimental or computational methods including but not limited to those with microscopy, diffraction, NMR, computer simulations, or biochemistry aimed at membrane associated or membrane embedded proteins or model membrane systems. These methods might be applied to study topics like membrane protein structure and function, membrane mediated or controlled signaling mechanisms, cell-cell communication via gap junctions, the behavior of proteins and lipids based on monolayer or bilayer systems, or genetic and regulatory mechanisms controlling membrane function. Research articles, short communications and reviews are all welcome. We also encourage authors to consider publishing ''negative'' results where experiments or simulations were well performed, but resulted in unusual or unexpected outcomes without obvious explanations. While we welcome connections to clinical studies, submissions that are primarily clinical in nature or that fail to make connections to the basic science issues of membrane structure, chemistry and function, are not appropriate for the journal. In a similar way, studies that are primarily descriptive and narratives of assays in a clinical or population study are best published in other journals. If you are not certain, it is entirely appropriate to write to us to inquire if your study is a good fit for the journal.
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