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Structural basis of ligand recognition at the human MT_1 melatonin receptor

机译：MT_1褪黑激素受体上配体识别的结构基础

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摘要

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms(1) by synchronization to environmental cues and is involved in diverse physiological processes(2) such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function(3). Melatonin is formed in the pineal gland in a light-regulated manner(4) by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness' by activating two high-affinity G-proteincoupled receptors, type 1A (MT1) and type 1B (MT2)(3,6). Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden(7). Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids(8,9), and is one of the most popular supplements in the United States(10). Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon(11), two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine(12,13). The structure of MT2 is described in an accompanying paper(14). Although the MT2 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT, mainly by strong aromatic stacking with Phel 79 and auxiliary hydrogen bonds with Asn162 and G1n181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.
机译：褪黑素（N-乙酰基-5-甲氧基色胺）是一种神经激素，通过与环境线索同步来维持昼夜节律（1），并参与多种生理过程（2），例如血压和核心体温的调节，致癌作用和免疫功能（3）。褪黑素以光调节的方式在松果体中形成（4），由5-羟色胺（5-HT或5-羟色胺）进行酶促转化，并通过激活两个高亲和力的G蛋白偶联受体1A来调节睡眠和清醒。 （MT1）和类型1B（MT2）（3,6）。轮班工作，旅行和无处不在的人工照明会破坏自然的昼夜节律。结果，睡眠障碍影响了现代社会的大量人口，并造成了可观的经济负担（7）。非处方褪黑素被广泛用于缓解时差反应，是苯二氮卓类药物和其他助眠剂的安全替代品（8,9），并且是美国最受欢迎的补品之一（10）。在这里，我们提出了MT1的高分辨率室温X射线自由电子激光（XFEL）结构，该结构与以下四种激动剂配合使用：失眠药物ramelteon（11），两种褪黑激素类似物和褪黑激素-5-羟色胺混合抗抑郁药agomelatine（12） ，13）。 MT2的结构在随附的论文中有描述（14）。尽管MT2和5-HT受体具有相似的内源性配体，阿戈美拉汀同时作用于这两种受体，但这些受体在其配体袋的结构和组成上存在显着差异。在MT1中，通过细胞外环2将与配体口袋的接触与溶剂紧密密封，在跨膜螺旋IV和V之间仅留下一条狭窄的通道将其连接至脂质双层。结合位点非常紧凑，配体与MT相互作用，主要是通过与Phel 79的强芳族堆积以及与Asn162和G1n181的辅助氢键形成。我们的结构为非脂质受体提供了非典型配体进入的意外实例，奠定了褪黑激素受体识别配体的分子基础，并有助于设计未来的工具化合物和治疗剂，同时将它们与5-HT受体进行比较对G蛋白偶联受体的进化和多药理学的见解。

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  • 来源
    《Nature》 |2019年第7755期|284-288|共5页
  • 作者

    Stauch Benjamin; Johansson Linda C.; McCorvy John D.; Patel Nilkanth; Han Gye Won; Huang Xi-Ping; Gati Cornelius; Batyuk Alexander; Slocum Samuel T.; Ishchenko Andrii; Brehm Wolfgang; White Thomas A.; Michaelian Nairie; Madsen Caleb; Zhu Lan; Grant Thomas D.; Grandner Jessica M.; Shiriaeva Anna; Olsen Reid H. J.; Tribo Alexandra R.; Yous Said; Stevens Raymond C.; Weierstall Uwe; Katritch Vsevolod; Roth Bryan L.; Liu Wei; Cherezov Vadim;

  • 作者单位

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA|Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90007 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA|Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27515 USA;

    SLAC Natl Accelerator Lab, Biosci Div, Menlo Pk, CA USA|Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA;

    SLAC Natl Accelerator Lab, Linac Coherent Light Source, Menlo Pk, CA USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    DESY, Ctr Free Electron Laser Sci, Hamburg, Germany;

    DESY, Ctr Free Electron Laser Sci, Hamburg, Germany;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA;

    Arizona State Univ, Sch Mol Sci, Tempe, AZ 85281 USA|Arizona State Univ, Biodesign Ctr Appl Struct Discovery, Biodesign Inst, Tempe, AZ 85281 USA;

    SUNY Buffalo, Hauptman Woodward Inst, Dept Biol Struct, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90007 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA;

    Univ Lille, INSERM, CHU Lille, UMR S 1172,JPArc,Ctr Rech Jean Pierre AUBERT Neur, Lille, France;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90007 USA;

    Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA|Arizona State Univ, Sch Mol Sci, Tempe, AZ 85281 USA|Arizona State Univ, Biodesign Ctr Appl Struct Discovery, Biodesign Inst, Tempe, AZ 85281 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90007 USA;

    Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA|Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27515 USA|Univ N Carolina, Div Chem Biol & Med Chem, Eshelman Sch Pharm, Chapel Hill, NC 27515 USA;

    Arizona State Univ, Sch Mol Sci, Tempe, AZ 85281 USA|Arizona State Univ, Biodesign Ctr Appl Struct Discovery, Biodesign Inst, Tempe, AZ 85281 USA;

    Univ Southern Calif, Bridge Inst, USC Michelson Ctr Convergent Biosci, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Chem, Los Angeles, CA 90007 USA|Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90007 USA;

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