Shahane Ganesh, Parsania Chirag, Sengupta Durba, Joshi Manali
CSIR-National Chemical Laboratory, Pune, India.
Bioinformatics Center, University of Pune, Pune, India.
PLoS Comput Biol. 2014 Dec 11;10(12):e1004006. doi: 10.1371/journal.pcbi.1004006. eCollection 2014 Dec.
The human β2-adrenergic receptor (β2AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, β2AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of β2AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the β2AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N-terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N-terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients.
人β2-肾上腺素能受体（β2AR）是G蛋白偶联受体（GPCR）家族的成员之一，在支气管平滑肌细胞中表达。在激动剂激活后，β2AR可引起哮喘患者支气管扩张并缓解症状。β2AR第16位的N端多态性（Arg16Gly）备受关注，因为它与对沙丁胺醇（激动剂）治疗反应的差异有关。尽管β2AR是研究较为深入的GPCR之一，但所有现有的实验结构中均缺少含有该突变的N端。这项工作的目标是使用结构建模和原子分子动力学模拟研究N端变体之间的分子水平差异。我们的模拟结果表明，精氨酸变体的N端区域比甘氨酸变体表现出更大的动力学，导致不同的位置排列。此外，N端区域的位置和动力学进一步影响配体结合位点的可及性。有趣的是，在配体结合位点也观察到远程效应，与精氨酸变体相比，甘氨酸变体中的配体结合位点略大，导致沙丁胺醇优先与甘氨酸变体对接。因此，这项研究揭示了变体之间的关键差异，为理解哮喘患者的可变药物反应提供了分子框架。
