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XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity.
Johansson, Linda C; Stauch, Benjamin; McCorvy, John D; Han, Gye Won; Patel, Nilkanth; Huang, Xi-Ping; Batyuk, Alexander; Gati, Cornelius; Slocum, Samuel T; Li, Chufeng; Grandner, Jessica M; Hao, Shuming; Olsen, Reid H J; Tribo, Alexandra R; Zaare, Sahba; Zhu, Lan; Zatsepin, Nadia A; Weierstall, Uwe; Yous, Saïd; Stevens, Raymond C; Liu, Wei; Roth, Bryan L; Katritch, Vsevolod; Cherezov, Vadim.
Afiliación
  • Johansson LC; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Stauch B; 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.
  • Han GW; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Patel N; 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.
  • Batyuk A; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Gati C; Department of Chemistry, 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.
  • Li C; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
  • Grandner JM; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hao S; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Olsen RHJ; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
  • Tribo AR; Bioscience Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
  • Zaare S; Department of Structural Biology, Stanford University, Stanford, CA, USA.
  • Zhu L; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Zatsepin NA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Weierstall U; Department of Physics, Arizona State University, Tempe, AZ, USA.
  • Yous S; School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
  • Stevens RC; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Liu W; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
  • Roth BL; Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
  • Katritch V; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
  • Cherezov V; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nature ; 569(7755): 289-292, 2019 05.
Article en En | MEDLINE | ID: mdl-31019305
The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns3. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer3, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature7) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure8 of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [3H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Modelos Moleculares / Receptor de Melatonina MT2 / Electrones / Rayos Láser Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Modelos Moleculares / Receptor de Melatonina MT2 / Electrones / Rayos Láser Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos