6me2 | pdb_00006me2
XFEL crystal structure of human melatonin receptor MT1 in complex with ramelteon
Structural highlights
FunctionQ9V2J8_PYRAB MTR1A_HUMAN High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. Publication Abstract from PubMedMelatonin (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 (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 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. Structural basis of ligand recognition at the human MT1 melatonin receptor.,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 Nature. 2019 May;569(7755):284-288. doi: 10.1038/s41586-019-1141-3. Epub 2019 Apr, 24. PMID:31019306[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
