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Structural basis of ligand recognition at the human MT_1 melatonin receptor

机译：人MT_1褪黑激素受体中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：褪黑激素（N-乙酰基-5-甲氧基氧基胺）是一种神经核心，其通过与环境提示同步维持昼夜生族，并参与各种生理过程（2），例如血压和核心体温，肿瘤发生和免疫功能（3）。通过从5-羟基特胺（5-HT或5- HT或羟色胺）的酶促转化，通过激活两个高亲和力G-蛋白燃烧受体，在酶促转化中以光调节（4）以光调节的方式（4）形成褪黑激素。 （MT1）和1B型（MT2）（3,6）。转移工作，旅行和无处不在的人工照明可以破坏自然昼夜节律;因此，睡眠障碍影响了现代社会中的大量人口，构成了相当大的经济负担（7）。反逆褪黑激素广泛用于缓解喷射滞后，作为苯二氮卓和其他睡眠辅助脂肪（8,9）的更安全的替代品，是美国最受欢迎的补充剂之一（10）。在这里，我们将高分辨率室温X射线自由电子激光器（XFEL）结构与四个激动剂（11），两种褪黑激素类似物，两种褪黑激素 - 血清素抗抑郁症（12 ，13）。 MT2的结构在附带的纸张（14）中描述。虽然MT2和5-HT受体具有相似的内源性配体，并且胍啉在两个受体上作用，受体在其配体袋的结构和组合物中显着不同;在MT1中，通过细胞外环2将对配体袋的进入从溶剂中密封，只留在将其连接到脂质双层的跨膜螺旋IV和V之间的窄通道。结合位点非常紧凑，配体与MT相互作用，主要是通过用诸如N162和G1N181的强烈芳族堆叠和辅助氢键。我们的结构提供了非脂质受体的非典型配体进入的意想不到的例子，使褪黑激素受体奠定了配体识别的分子基础，并促进了未来工具化合物和治疗剂的设计，而其与5-HT受体的比较识别G蛋白偶联受体的进化和多药地。

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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;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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