Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions—both therapeutic and hallucinogenic—are not understood, although activation of the 5-HT_2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH—a prototypical hallucinogen—in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

迷幻剂如麦角酸二乙酰胺 (LSD)、裸盖菇素和取代的N-苄基苯基烷基胺被广泛用于娱乐，裸盖菇素被认为是许多神经精神疾病的治疗剂，包括抑郁症、焦虑症和药物滥用。尽管激活了 5-HT _2A，但迷幻剂如何调节它们的作用——包括治疗作用和致幻作用——尚不清楚血清素受体 (HTR2A) 是关键。为了获得对迷幻作用的分子见解，我们通过冷冻电子显微镜 (cryo-EM) 确定了 HTR2A 与 25-CN-NBOH（一种原型致幻剂）与工程化 Gαq 异源三聚体结合的活性状态结构。我们还获得了与抑制素偏向配体 LSD 或反向激动剂甲硫氧嘧啶复合的 HTR2A 的 X 射线晶体结构。这些结构的比较揭示了负责 HTR2A-Gαq 蛋白质相互作用的决定因素以及参与活性状态转换的构象重排。考虑到致幻剂的潜在治疗作用，这些发现可能会加速发现用于治疗各种神经精神疾病的更具选择性的药物。