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Title: Structural basis of ligand recognition at the human MT1 melatonin receptor

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms by synchronization to environmental cues and is involved in diverse physiological processes such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function. Melatonin is formed in the pineal gland in a light-regulated manner by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT 1) and type 1B (MT 2). 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. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids and is one of the most popular supplements in the United States. Here in this paper, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT 1 in complex with four agonists: the insomnia drug ramelteon, two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine. The structure of MT 2 is described in an accompanying paper. Although the MT 1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors,more » the receptors differ markedly in the structure and composition of their ligand pockets; in MT 1, 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 1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. 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.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [3];  [4];  [5];  [3];  [1];  [6];  [6];  [1];  [7];  [7];  [8];  [1];  [1];  [3];  [3] more »;  [9];  [1];  [7];  [1];  [3];  [7];  [1] « less
  1. Univ. of Southern California, Los Angeles, CA (United States)
  2. Univ. of North Carolina, Chapel Hill, NC (United States); Medical College of Wisconsin, Milwaukee, WI (United States)
  3. Univ. of North Carolina, Chapel Hill, NC (United States)
  4. SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States)
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
  6. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science
  7. Arizona State Univ., Tempe, AZ (United States)
  8. Univ. at Buffalo, Buffalo, NY (United States)
  9. Univ. of Lille,Lille (France)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1528824
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 569; Journal Issue: 7755; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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, Saïd, Stevens, Raymond C., Weierstall, Uwe, Katritch, Vsevolod, Roth, Bryan L., Liu, Wei, and Cherezov, Vadim. Structural basis of ligand recognition at the human MT1 melatonin receptor. United States: N. p., 2019. Web. doi:10.1038/s41586-019-1141-3.
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, Saïd, Stevens, Raymond C., Weierstall, Uwe, Katritch, Vsevolod, Roth, Bryan L., Liu, Wei, & Cherezov, Vadim. Structural basis of ligand recognition at the human MT1 melatonin receptor. United States. doi:10.1038/s41586-019-1141-3.
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, Saïd, Stevens, Raymond C., Weierstall, Uwe, Katritch, Vsevolod, Roth, Bryan L., Liu, Wei, and Cherezov, Vadim. Wed . "Structural basis of ligand recognition at the human MT1 melatonin receptor". United States. doi:10.1038/s41586-019-1141-3.
@article{osti_1528824,
title = {Structural basis of ligand recognition at the human MT1 melatonin receptor},
author = {Stauch, Benjamin and Johansson, Linda C. and McCorvy, John D. and Patel, Nilkanth and Han, Gye Won and Huang, Xi-Ping and Gati, Cornelius and Batyuk, Alexander and Slocum, Samuel T. and Ishchenko, Andrii and Brehm, Wolfgang and White, Thomas A. and Michaelian, Nairie and Madsen, Caleb and Zhu, Lan and Grant, Thomas D. and Grandner, Jessica M. and Shiriaeva, Anna and Olsen, Reid H. J. and Tribo, Alexandra R. and Yous, Saïd and Stevens, Raymond C. and Weierstall, Uwe and Katritch, Vsevolod and Roth, Bryan L. and Liu, Wei and Cherezov, Vadim},
abstractNote = {Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms by synchronization to environmental cues and is involved in diverse physiological processes such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function. Melatonin is formed in the pineal gland in a light-regulated manner by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2). 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. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids and is one of the most popular supplements in the United States. Here in this paper, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon, two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine. The structure of MT2 is described in an accompanying paper. Although the MT1 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 MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. 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.},
doi = {10.1038/s41586-019-1141-3},
journal = {Nature (London)},
number = 7755,
volume = 569,
place = {United States},
year = {2019},
month = {4}
}

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