Molecular mechanism of the wake-promoting agent TAK-925.
Molecular mechanism of the wake-promoting agent TAK-925.
复制标题
促醒剂TAK-925的分子机制。
DOI：
10.1038/s41467-022-30601-3
复制
发表时间：
2022-05-25
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
OX 2食欲素受体（OX 2 R）是大脑中高度表达的G蛋白偶联受体（GPCR），可调节人类的觉醒和昼夜节律。OX 2 R的拮抗作用是失眠药物的经证实的治疗策略，而OX 2 R的激动作用是1型发作性睡病的潜在有效方法，其特征在于食欲素能神经元的死亡。直到最近，OX 2 R的激动作用一直被认为是“不可治疗的”。我们利用OX 2 R-G蛋白复合物的冷冻电子显微镜来确定第一个临床测试的OX 2 R激动剂TAK-925如何以高度选择性的方式激活OX 2 R。具有Gq模拟物或Gi的TAK-925结合OX 2 R的两种结构表明，TAK-925在拮抗剂占据的相同位点结合，但与跨膜螺旋相互作用以触发激活微动开关。我们的结构和诱变数据表明，TAK-925的选择性是由正构口袋中OX 1和OX 2受体亚型之间的细微差异介导的。最后，G蛋白结合界面相互作用极性的差异有助于合理化OX 2 R对Gq信号传导的偶联选择性。本文提供的TAK-925结合、活化和选择性机制将有助于理解小分子OX 2 R激动剂对发作性睡病和其他昼夜节律疾病的疗效。OX 2食欲素受体（OX 2 R）是调节人类觉醒和昼夜节律的脑GPCR，并且是失眠和发作性睡病的潜在药物靶点。在这里，作者使用cryo-EM来确定第一个临床测试的OX 2 R激动剂TAK-925如何以选择性方式激活OX 2 R。
The OX2 orexin receptor (OX2R) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OX2R is a proven therapeutic strategy for insomnia drugs, and agonism of OX2R is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OX2R had been considered ‘undruggable.’ We harness cryo-electron microscopy of OX2R-G protein complexes to determine how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a highly selective manner. Two structures of TAK-925-bound OX2R with either a Gq mimetic or Gi reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925’s selectivity is mediated by subtle differences between OX1 and OX2 receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OX2R’s coupling selectivity for Gq signaling. The mechanisms of TAK-925’s binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OX2R agonists for narcolepsy and other circadian disorders. The OX2 orexin receptor (OX2R) is a brain GPCR that regulates wakefulness and circadian rhythms in humans, and a potential drug target in insomnia and narcolepsy. Here, the authors use cryo-EM to determine how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a selective manner.
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影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
通讯作者：
Kobilka BK
DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Hong C;Byrne NJ;Zamlynny B;Tummala S;Xiao L;Shipman JM;Partridge AT;Minnick C;Breslin MJ;Rudd MT;Stachel SJ;Rada VL;Kern JC;Armacost KA;Hollingsworth SA;O'Brien JA;Hall DL;McDonald TP;Strickland C;Brooun A;Soisson SM;Hollenstein K
通讯作者：
Hollenstein K
胆囊收缩素A受体的配体识别和G蛋白偶联选择性
影响因子：
14.8
作者：
Liu Q;Yang D;Zhuang Y;Croll TI;Cai X;Dai A;He X;Duan J;Yin W;Ye C;Zhou F;Wu B;Zhao Q;Xu HE;Wang MW;Jiang Y
通讯作者：
Jiang Y
影响因子：
64.5
作者：
Inoue, Asuka;Raimondi, Francesco;Russell, Robert B.
通讯作者：
Russell, Robert B.