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Nature. 2019 May;569(7755):289-292. doi: 10.1038/s41586-019-1144-0. Epub 2019 Apr 24.

XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity.

Johansson LC1,2, Stauch B1,2, McCorvy JD3,4, Han GW1,2, Patel N1,5, Huang XP3,6, Batyuk A7, Gati C8,9, Slocum ST3,6, Li C10,11, Grandner JM1,5, Hao S1,2, Olsen RHJ3, Tribo AR3, Zaare S10, Zhu L11, Zatsepin NA10,11, Weierstall U10,11, Yous S12, Stevens RC1,2,5, Liu W11, Roth BL13,14,15, Katritch V16,17,18, Cherezov V19,20,21.

Author information

1
Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
2
Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
3
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
5
Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
6
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
7
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
8
Bioscience Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
9
Department of Structural Biology, Stanford University, Stanford, CA, USA.
10
Department of Physics, Arizona State University, Tempe, AZ, USA.
11
School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
12
Université de Lille, CHU Lille, Inserm, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.
13
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
14
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
15
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
16
Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA. katritch@usc.edu.
17
Department of Chemistry, University of Southern California, Los Angeles, CA, USA. katritch@usc.edu.
18
Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. katritch@usc.edu.
19
Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA. cherezov@usc.edu.
20
Department of Chemistry, University of Southern California, Los Angeles, CA, USA. cherezov@usc.edu.
21
Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. cherezov@usc.edu.

Abstract

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.

PMID:
31019305
DOI:
10.1038/s41586-019-1144-0

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