褪黑激素受体的结构见解。,The FEBS Journal

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褪黑激素受体的结构见解。
The FEBS Journal ( IF 5.5 ) Pub Date : 2019-11-23 , DOI: 10.1111/febs.15128
Benjamin Stauch _{1,

2} , Linda C Johansson _{1,

2} , Vadim Cherezov _{1,

2,

3}

Affiliation

人类褪黑激素 G 蛋白偶联受体 MT1 和 MT2 参与建立和维持昼夜节律的期待已久的高分辨率结构是使用 X 射线与两种褪黑激素类似物和两种批准的抗失眠和抗抑郁药物复合获得的自由电子激光串行飞秒晶体学。这些结构揭示了褪黑激素受体的整体构象和不寻常的结构特征，以及它们的配体结合位点和褪黑激素药效团，从而提供了对受体亚型选择性的见解。这些结构揭示了一个封闭的正构配体结合位点，具有一个用于配体进入两种受体的膜埋通道，以及一个额外的假定配体从细胞外侧进入 MT2 的路径。这种意想不到的配体进入模式有助于促进褪黑激素受体与其同源配体结合的高度特异性，并排除结构相似的分子，例如褪黑激素的生物合成前体血清素。最后，MT2 结构允许准确定位 2 型糖尿病相关的单核苷酸多态性，其中观察到蛋白质-膜界面上螺旋 I 和 II 中的残基聚集，这可能会影响受体寡聚化。鉴于 MT1 和 MT2 与调节性褪黑激素辅助受体 GPR50 的不同相互作用，进一步讨论了受体寡聚化的作用。

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Structural insights into melatonin receptors.

The long-anticipated high-resolution structures of the human melatonin G protein-coupled receptors MT1 and MT2 , involved in establishing and maintaining circadian rhythm, were obtained in complex with two melatonin analogs and two approved anti-insomnia and antidepression drugs using X-ray free-electron laser serial femtosecond crystallography. The structures shed light on the overall conformation and unusual structural features of melatonin receptors, as well as their ligand binding sites and the melatonergic pharmacophore, thereby providing insights into receptor subtype selectivity. The structures revealed an occluded orthosteric ligand binding site with a membrane-buried channel for ligand entry in both receptors, and an additional putative ligand entry path in MT2 from the extracellular side. This unexpected ligand entry mode contributes to facilitating the high specificity with which melatonin receptors bind their cognate ligand and exclude structurally similar molecules such as serotonin, the biosynthetic precursor of melatonin. Finally, the MT2 structure allowed accurate mapping of type 2 diabetes-related single-nucleotide polymorphisms, where a clustering of residues in helices I and II on the protein-membrane interface was observed which could potentially influence receptor oligomerization. The role of receptor oligomerization is further discussed in light of the differential interaction of MT1 and MT2 with GPR50, a regulatory melatonin coreceptor. The melatonin receptor structures will facilitate design of selective tool compounds to further dissect the specific physiological function of each receptor subtype as well as provide a structural basis for next-generation sleeping aids and other drugs targeting these receptors with higher specificity and fewer side effects.

更新日期：2019-11-23

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