Structural basis of the ligand binding and signaling mechanism of melatonin receptors.
Structural basis of the ligand binding and signaling mechanism of melatonin receptors.
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褪黑激素受体配体结合和信号传导机制的结构基础
DOI：
10.1038/s41467-022-28111-3
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发表时间：
2022-01-24
影响因子：
16.6
通讯作者：
Tao Y
中科院分区：
文献类型：
--
作者：
Wang Q;Lu Q;Guo Q;Teng M;Gong Q;Li X;Du Y;Liu Z;Tao Y
褪黑激素受体（MT 1和MT 2在人类）是家庭A G蛋白偶联受体，响应神经激素褪黑激素调节昼夜节律和睡眠。已经做出了许多努力来开发靶向褪黑激素受体的药物以用于治疗失眠、昼夜节律紊乱和癌症。然而，设计亚型选择性褪黑激素能药物仍然具有挑战性。在这里，我们报告了MT 1-Gi信号复合物与2-碘褪黑激素和雷美琼和MT 2-Gi信号复合物与雷美琼的冷冻电镜结构。这些结构，连同报道的功能数据，揭示了虽然MT 1和MT 2具有高度相似的正构配体结合口袋，但它们也显示出可用于设计亚型选择性药物的独特特征。MT 1和MT 2中独特的结构基序介导了在细胞质侧具有特别宽的开口的结构重排。Gi参与MT 1和MT 2共享的受体核心，并呈现出与其他Gi复合物中的构象不同的构象。总之，我们的研究结果为设计褪黑激素能药物提供了新的线索，并进一步了解G蛋白偶联机制。褪黑激素受体（MT 1和MT 2）是褪黑激素的靶点，褪黑激素是参与昼夜节律和睡眠调节的主要神经激素。在这里，作者描述了2-碘褪黑激素和雷美替酮结合的MT 1-Gi和MT 2-Gi的结构，揭示了MT 1和MT 2在配体结合口袋内具有独特的特征。
Melatonin receptors (MT1 and MT2 in humans) are family A G protein–coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made to develop drugs targeting melatonin receptors for the treatment of insomnia, circadian rhythm disorder, and cancer. However, designing subtype-selective melatonergic drugs remains challenging. Here, we report the cryo-EM structures of the MT1–Gi signaling complex with 2-iodomelatonin and ramelteon and the MT2–Gi signaling complex with ramelteon. These structures, together with the reported functional data, reveal that although MT1 and MT2 possess highly similar orthosteric ligand-binding pockets, they also display distinctive features that could be targeted to design subtype-selective drugs. The unique structural motifs in MT1 and MT2 mediate structural rearrangements with a particularly wide opening on the cytoplasmic side. Gi is engaged in the receptor core shared by MT1 and MT2 and presents a conformation deviating from those in other Gi complexes. Together, our results provide new clues for designing melatonergic drugs and further insights into understanding the G protein coupling mechanism. Melatonin receptors (MT1 and MT2) are the targets for melatonin, the major neurohormone involved in circadian rhythm and sleep regulation. Here the authors describe the structures of 2-iodomelatonin and ramelteon bound MT1–Gi and MT2-Gi, revealing that MT1 and MT2 possess distinctive features within the ligand-binding pocket.
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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
影响因子：
5.6
作者：
Carrillo-Vico A;Lardone PJ;Alvarez-Sánchez N;Rodríguez-Rodríguez A;Guerrero JM
通讯作者：
Guerrero JM
影响因子：
7.3
作者：
Cecon, Erika;Oishi, Atsuro;Jockers, Ralf
通讯作者：
Jockers, Ralf
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
影响因子：
5.8
作者：
Chan, King H.;Tse, Lap H.;Wong, Yung H.
通讯作者：
Wong, Yung H.