Open AccessStructural basis of ligand recognition at the human MT1 melatonin receptor
Author(s) -
Benjamin Stauch,
Linda C. Johansson,
John D. McCorvy,
Nilkanth Patel,
Gye Won Han,
Xi Ping Huang,
Cornelius Gati,
A. Batyuk,
Samuel T. Slocum,
Andrii Ishchenko,
Wolfgang Brehm,
Thomas A. White,
Nairie Michaelian,
Caleb Madsen,
Liya Zhu,
Thomas D. Grant,
Jessica M. Grandner,
Anna Shiriaeva,
Reid H.J. Olsen,
Alexandra R. Tribo,
Saı̈d Yous,
Raymond C. Stevens,
Uwe Weierstall,
Vsevolod Katritch,
Bryan L. Roth,
Wei Liu,
Vadim Cherezov
Publication year - 2019
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-019-1141-3
Subject(s) - melatonin , receptor , circadian rhythm , serotonin , ligand (biochemistry) , 5 ht receptor , melatonin receptor , medicine , endocrinology , biology , population , microbiology and biotechnology , biophysics , chemistry , biochemistry , environmental health
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 5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT 1 ) and type 1B (MT 2 ) 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 MT 1 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 MT 2 is described in an accompanying paper 14 . Although the MT 1 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 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.