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Structural basis of ligand recognition at the human MT1 melatonin receptor.
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.
Afiliación
  • Stauch B; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Johansson LC; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • McCorvy JD; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Patel N; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Han GW; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Huang XP; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Gati C; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Batyuk A; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
  • Slocum ST; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Ishchenko A; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Brehm W; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • White TA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Michaelian N; SLAC National Accelerator Laboratory, Bioscience Division, Menlo Park, CA, USA.
  • Madsen C; Stanford University, Department of Structural Biology, Stanford, CA, USA.
  • Zhu L; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
  • Grant TD; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Grandner JM; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Shiriaeva A; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Olsen RHJ; Center for Free-Electron Laser Science, DESY, Hamburg, Germany.
  • Tribo AR; Center for Free-Electron Laser Science, DESY, Hamburg, Germany.
  • Yous S; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Stevens RC; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Weierstall U; Department of Physics, Arizona State University, Tempe, AZ, USA.
  • Katritch V; School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
  • Roth BL; Hauptman-Woodward Institute, Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
  • Liu W; Bridge Institute,USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Cherezov V; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
Nature ; 569(7755): 284-288, 2019 05.
Article en En | MEDLINE | ID: mdl-31019306
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.
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Texto completo: 1 Colección: 01-internacional Asunto principal: Modelos Moleculares / Receptor de Melatonina MT1 / Electrones / Rayos Láser Límite: Humans Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Asunto principal: Modelos Moleculares / Receptor de Melatonina MT1 / Electrones / Rayos Láser Límite: Humans Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos