G蛋白偶联受体
生物化学
配体(生物化学)
小分子
变构酶
立体化学
结构生物学
跨膜结构域
细胞生物学
作者
Xiangyu Liu,Jonas Kaindl,Magdalena Korczynska,Anne Stößel,Daniela G. Dengler,Markus Stanek,Harald Hübner,Mary Jo Clark,Jake Mahoney,Rachel A. Matt,Xinyu Xu,Kunio Hirata,Brian K. Shoichet,Roger K. Sunahara,Brian K. Kobilka,Peter Gmeiner
标识
DOI:10.1038/s41589-020-0549-2
摘要
Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β2-adrenergic receptor (β2AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E1223.41 and the backbone carbonyls of V2065.45 and S2075.46. The AS408 binding site is adjacent to a previously identified molecular switch for β2AR activation formed by I3.40, P5.50 and F6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists. A negative allosteric modulator of the G-protein-coupled receptor β2-adrenergic receptor binds to a membrane-facing surface adjacent to a molecular switch for receptor activation, and its binding disrupts a water-mediated polar network stabilizing an inactive switch conformation.
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