Orexin(下视丘分泌素)系统调控人类睡眠和唤醒，Orexin受体拮抗物被看做是有希望用来治疗失眠的药物。本文作者获得了在suvorexant (一种 “双Orexin受体拮抗物”抗失眠药物)存在情况下的人OX2Orexin受体的X-射线晶体结构。该结构为了解 “双Orexin受体拮抗物”的结合提供了一个分子框架。作者采用两个不同的对接程序来预测具有不同核心结构的其他三种拮抗物会怎样与这一 “G-蛋白耦合受体”结合。

  原文链接：Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant

The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans1. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia2. The human OX2receptor (OX2R) belongs to the β branch of the rhodopsin family of GPCRs3, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant4. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous π-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.