Author
Listed:
- Benjamin Stauch
(University of Southern California
University of Southern California)
- Linda C. Johansson
(University of Southern California
University of Southern California)
- John D. McCorvy
(University of North Carolina at Chapel Hill
Medical College of Wisconsin)
- Nilkanth Patel
(University of Southern California
University of Southern California)
- Gye Won Han
(University of Southern California
University of Southern California)
- Xi-Ping Huang
(University of North Carolina at Chapel Hill
University of North Carolina at Chapel Hill)
- Cornelius Gati
(Bioscience Division
Stanford University, Department of Structural Biology)
- Alexander Batyuk
(SLAC National Accelerator Laboratory)
- Samuel T. Slocum
(University of North Carolina at Chapel Hill)
- Andrii Ishchenko
(University of Southern California
University of Southern California)
- Wolfgang Brehm
(Center for Free-Electron Laser Science, DESY)
- Thomas A. White
(Center for Free-Electron Laser Science, DESY)
- Nairie Michaelian
(University of Southern California
University of Southern California)
- Caleb Madsen
(Arizona State University)
- Lan Zhu
(Arizona State University)
- Thomas D. Grant
(University at Buffalo)
- Jessica M. Grandner
(University of Southern California
University of Southern California)
- Anna Shiriaeva
(University of Southern California
University of Southern California)
- Reid H. J. Olsen
(University of North Carolina at Chapel Hill)
- Alexandra R. Tribo
(University of North Carolina at Chapel Hill)
- Saïd Yous
(Univ Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer)
- Raymond C. Stevens
(University of Southern California
University of Southern California
University of Southern California)
- Uwe Weierstall
(Arizona State University
Arizona State University)
- Vsevolod Katritch
(University of Southern California
University of Southern California
University of Southern California)
- Bryan L. Roth
(University of North Carolina at Chapel Hill
University of North Carolina at Chapel Hill
University of North Carolina at Chapel Hill)
- Wei Liu
(Arizona State University)
- Vadim Cherezov
(University of Southern California
University of Southern California
University of Southern California)
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 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)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 burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. 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.
Suggested Citation
Benjamin Stauch & Linda C. Johansson & John D. McCorvy & Nilkanth Patel & Gye Won Han & Xi-Ping Huang & Cornelius Gati & Alexander Batyuk & Samuel T. Slocum & Andrii Ishchenko & Wolfgang Brehm & Thoma, 2019.
"Structural basis of ligand recognition at the human MT1 melatonin receptor,"
Nature, Nature, vol. 569(7755), pages 284-288, May.
Handle:
RePEc:nat:nature:v:569:y:2019:i:7755:d:10.1038_s41586-019-1141-3
DOI: 10.1038/s41586-019-1141-3
Download full text from publisher
As the access to this document is restricted, you may want to search for a different version of it.
Citations
Citations are extracted by the
CitEc Project, subscribe to its
RSS feed for this item.
Cited by:
- Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024.
"Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode,"
Nature Communications, Nature, vol. 15(1), pages 1-10, December.
- Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022.
"Fusion protein strategies for cryo-EM study of G protein-coupled receptors,"
Nature Communications, Nature, vol. 13(1), pages 1-11, December.
- Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023.
"Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding,"
Nature Communications, Nature, vol. 14(1), pages 1-13, December.
- Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021.
"Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5,"
Nature Communications, Nature, vol. 12(1), pages 1-11, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:569:y:2019:i:7755:d:10.1038_s41586-019-1141-3. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.