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 E122^3.41 and the backbone carbonyls of V206^5.45 and S207^5.46. The AS408 binding site is adjacent to a previously identified molecular switch for β₂AR activation formed by I^3.40, P^5.50 and F^6.44. 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.

大多数作用于 G 蛋白偶联受体的药物都靶向天然激素或神经递质结合的正位结合袋。人们对寻找这些靶标的变构配体非常感兴趣，因为它们调节生理信号并且有望比正构配体更具选择性。在这里，我们描述了一种新开发的 β ₂ -肾上腺素能受体 (β ₂ AR) 变构调节剂 AS408，如 X 射线晶体学所示，它与跨膜片段 3 和 5 的面向膜的表面结合。 AS408 破坏涉及 E122 ^3.41以及 V206 ^5.45和 S207 ^5.46的主链羰基的水介导的极性网络。 AS408 结合位点邻近先前鉴定的由 I ^3.40 、 P ^5.50和 F ^6.44形成的用于 β ₂ AR 激活的分子开关。该结构揭示了 AS408 如何稳定该开关的非活性构象，从而充当激动剂的负变构调节剂和反向激动剂的正变构调节剂。