Faculty Collaboration Database

Structural basis of ligand recognition at the human MT₁ melatonin receptor. Nature 2019 May;569(7755):284-288

Date

04/26/2019

Pubmed ID

31019306

Pubmed Central ID

PMC6696938

DOI

10.1038/s41586-019-1141-3

Scopus ID

2-s2.0-85064887125 (requires institutional sign-in at Scopus site)   186 Citations

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 aids^8,9, 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 agomelatine^12,13. 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.

Author List

Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP, Gati C, Batyuk A, Slocum ST, Ishchenko A, Brehm W, White TA, Michaelian N, Madsen C, Zhu L, Grant TD, Grandner JM, Shiriaeva A, Olsen RHJ, Tribo AR, Yous S, Stevens RC, Weierstall U, Katritch V, Roth BL, Liu W, Cherezov V

Authors

Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Lan Zhu PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetamides
Amino Acid Sequence
Antidepressive Agents
Crystallization
Electrons
Humans
Indenes
Lasers
Ligands
Melatonin
Models, Molecular
Molecular Docking Simulation
Mutation
Naphthalenes
Receptor, Melatonin, MT1
Receptor, Serotonin, 5-HT2C
Structure-Activity Relationship
Substrate Specificity