Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences , University of São Paulo , Av. Prof. Lineu Prestes 580 , 05508-900 São Paulo - SP , Brazil.
Laboratory of Genetics and Molecular Cardiology, Heart Institute , University of São Paulo Medical School , Av. Dr. Enéas de Carvalho Aguiar 44 , 05403-900 São Paulo - SP , Brazil.
J Chem Inf Model. 2019 Feb 25;59(2):797-808. doi: 10.1021/acs.jcim.8b00628. Epub 2019 Feb 4.
Functional selectivity is a phenomenon observed in G protein-coupled receptors in which intermediate active-state conformations are stabilized by mutations or ligand binding, resulting in different sets of signaling pathways. Peptides capable of selectively activating β-arrestin, known as biased agonists, have already been characterized in vivo and could correspond to a new therapeutic approach for treatment of cardiovascular diseases. Despite the potential of biased agonism, the mechanism involved in selective signaling remains unclear. In this work, molecular dynamics simulations were employed to compare the conformational profile of the angiotensin II type 1 receptor (AT1R) crystal bound to angiotensin II, bound to the biased ligand TRV027, and in the apo form. Our results show that both ligands induce changes near the NPxxY motif in transmembrane domain 7 that are related to receptor activation. However, the biased ligand does not cause the rotamer toggle alternative positioning and displays an exclusive hydrogen-bonding pattern. Our work sheds light on the biased agonism mechanism and will help in the future design of novel biased agonists for AT1R.
功能选择性是 G 蛋白偶联受体中观察到的一种现象，其中中间活性构象通过突变或配体结合稳定，导致不同的信号通路。已经在体内表征了能够选择性激活β-arrestin 的肽，称为偏向激动剂，它们可能对应于心血管疾病治疗的新治疗方法。尽管偏向激动剂具有潜力，但选择性信号传递所涉及的机制仍不清楚。在这项工作中，我们使用分子动力学模拟来比较与血管紧张素 II 结合的血管紧张素 II 型 1 受体 (AT1R) 晶体、与偏向配体 TRV027 结合的 AT1R 晶体和apo 形式的 AT1R 晶体的构象特征。我们的结果表明，两种配体都在跨膜域 7 中的 NPxxY 基序附近诱导变化，这与受体激活有关。然而，偏向配体不会引起变构体切换替代定位，并且显示出独特的氢键模式。我们的工作阐明了偏向激动剂的作用机制，并将有助于未来设计用于 AT1R 的新型偏向激动剂。
