Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure
作者:Marta Busnelli、Gunnar Kleinau、Markus Muttenthaler、Stoytcho Stoev、Maurice Manning、Lucka Bibic、Lesley A. Howell、Peter J. McCormick、Simona Di Lascio、Daniela Braida、Mariaelvina Sala、G. Enrico Rovati、Tommaso Bellini、Bice Chini
DOI:10.1021/acs.jmedchem.6b00564
日期:2016.8.11
G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides
G 蛋白偶联受体的二聚体/寡聚体状态一直难以靶向。我们在此报告了由两种相同的催产素模拟物组成的二价配体,它们在体外诱导催产素受体 (OTR) 的 G 蛋白信号传导增加三个数量级,在体内的效力增加 100 倍和 40 倍在老鼠和斑马鱼的社会行为中。通过模拟跨膜螺旋 (TMH) 的合成肽的受体诱变和干扰实验,我们表明这种超强行为来自二价配体与基于 TMH1-TMH2 界面的二聚体受体的结合。此外,在这种排列中,只有具有明确间隔长度(~25 Å)的类似物才能精确地安装在二聚体的两个原体之间的通道状通道内。新发现的催产素二价配体代表了在神经发育和精神疾病中靶向二聚体 OTR 的强大工具,并且通常提供了解开 G 蛋白偶联受体二聚体特定排列的框架。