G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β2 adrenergic receptor (β2AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

中文翻译：

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X射线晶体结构揭示细胞内变构β2AR拮抗剂的作用机制

G 蛋白偶联受体 (GPCR) 对药物发现工作提出了挑战，因为正构口袋中的结构同源性很高，特别是对于单个亚家族中的 GPCR，例如九个肾上腺素能受体。变构配体可能与这些受体的保守性较低的区域结合，因此更有可能具有选择性。与强直激活或抑制信号传导的正构配体不同，变构配体调节对激素和神经递质的生理反应，因此可能具有较少的副作用。迄今为止发表的大多数 GPCR 晶体结构是用与正构拮抗剂结合的受体获得的，只有少数与变构配体结合的结构已被报道。化合物 15 (Cmpd-15) 是最近从 DNA 编码的小分子文库中分离出来的 β2 肾上腺素能受体 (β2AR) 的变构调节剂。正构β-肾上腺素能受体拮抗剂，称为β-受体阻滞剂，是世界上处方最多的药物之一，Cmpd-15 是第一个变构β-受体阻滞剂。Cmpd-15 表现出与激动剂的负协同性和与反向激动剂的正协同性。在这里，我们展示了与该调节剂的聚乙二醇-羧酸衍生物 (Cmpd-15PA) 结合的 β2AR 的结构。Cmpd-15PA 与主要由跨膜片段 1、2、6 和 7 以及细胞内环 1 和螺旋 8 的细胞质末端形成的口袋结合。