Structure of a Hallucinogen-Activated Gq-Coupled 5-HT(2A) Serotonin Receptor.
Structure of a Hallucinogen-Activated Gq-Coupled 5-HT(2A) Serotonin Receptor.
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DOI：
10.1016/j.cell.2020.08.024
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发表时间：
2020-09-17
期刊：
影响因子：
64.5
通讯作者：
Roth BL
中科院分区：
文献类型：
--
作者：
Kim K;Che T;Panova O;DiBerto JF;Lyu J;Krumm BE;Wacker D;Robertson MJ;Seven AB;Nichols DE;Shoichet BK;Skiniotis G;Roth BL
致幻剂如麦角酸二乙基酰胺（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、焦虑症和物质滥用。致幻剂是如何调节其治疗和致幻作用的尚不清楚，尽管5-HT 2A血清素受体（HTR 2A）的激活是关键。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）确定了与25-CN-NBOH结合的HTR 2A的活性状态结构，25-CN-NBOH是一种具有工程Gαq异源三聚体的原型致幻剂复合物。我们还获得了HTR 2A与抑制蛋白偏置配体LSD或反向激动剂甲硫替平复合的X射线晶体结构。这些结构的比较揭示了负责HTR 2A-G αq蛋白相互作用以及参与活性状态转变的构象重排的决定因素。考虑到致幻剂的潜在治疗作用，这些发现可以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。Roth等人从结构上揭示了致幻剂，包括LSD，psilocin，mescaline和各种N-BOH类似物，如何通过结合并激活其分子靶点，即与G蛋白Gαq偶联的5-羟色胺（5-HT）2A受体来介导其治疗和致幻作用。
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-HT2A 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. Roth et al. reveal structurally how psychedelics, including LSD, psilocin, mescaline, and various N-BOH analogs, mediate their therapeutic and hallucinogenic effects by binding to and activating their molecular target, the serotonin (5-HT) 2A receptor coupled with G-protein Gαq.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
4.7
作者：
Halberstadt AL;Sindhunata IS;Scheffers K;Flynn AD;Sharp RF;Geyer MA;Young JW
通讯作者：
Young JW
影响因子：
5.6
作者：
Allen WJ;Rizzo RC
通讯作者：
Rizzo RC
影响因子：
64.5
作者：
Inoue, Asuka;Raimondi, Francesco;Russell, Robert B.
通讯作者：
Russell, Robert B.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K