The β2-adrenergic receptor (β2AR) is a membrane-bound G-protein-coupled receptor and an important drug target for asthma. Clinical studies report that the population variant Gln27Glu is associated with a differential response to common asthma drugs, such as albuterol, isoproterenol and terbutaline. Interestingly, the 27th amino acid is positioned on the N-terminal region that is the most flexible and consequently the least studied part of the receptor. In this study, we probe the molecular origin of the differential drug binding by performing structural modeling and simulations of the wild-type (Gln) and variant (Glu) receptors followed by ensemble docking with the ligands, albuterol, isoproterenol and terbutaline. In line with clinical studies, the ligands were observed to interact preferentially with the Glu variant. Our results indicate that the Glu residue at the 27th position perturbs the network of electrostatic interactions that connects the N-terminal region to the binding site in the wild-type receptor. As a result, the Glu variant is observed to bind better to the three ligands tested in this study. Our study provides a structural basis to explain the variable drug response associated with the 27th position polymorphism in the β2AR and is a starting step to identify genotype-specific therapeutics.

中文翻译：

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β2-肾上腺素能受体Gln27Glu种群变异背后的差分动力学。

β2-肾上腺素能受体（β2AR）是膜结合的G蛋白偶联受体，是哮喘的重要药物靶标。临床研究报告说，人群变异Gln27Glu与常见的哮喘药物（如沙丁胺醇，异丙肾上腺素和特布他林）有不同的反应。有趣的是，第27个氨基酸位于N端区域，该区域是受体最灵活的部分，因此也是研究最少的部分。在这项研究中，我们通过对野生型（Gln）和变异型（Glu）受体进行结构建模和模拟，然后与配体，沙丁胺醇，异丙肾上腺素和特布他林进行整体对接，来探索差异药物结合的分子起源。与临床研究一致，观察到配体优先与Glu变体相互作用。我们的结果表明，第27位的Glu残基干扰了静电相互作用的网络，该网络将N末端区域连接到野生型受体的结合位点。结果，观察到Glu变体与本研究中测试的三个配体更好地结合。我们的研究为解释与β2AR中第27位多态性相关的可变药物反应提供了结构基础，并且是鉴定基因型特异性治疗剂的起始步骤。