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Cell. 2018 Feb 8;172(4):719-730.e14. doi: 10.1016/j.cell.2018.01.001. Epub 2018 Feb 1.

5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
4
Laboratory of Physical Chemistry of Polymers and Membranes, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH B3 495 (Bâtiment CH) Station 6, Lausanne 1015, Switzerland.
5
Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center, University of Southern California, Los Angeles, CA 90089, USA; Moscow Institute of Physics and Technology, Dolgoprudny 141700, Russia.
6
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
7
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
8
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
9
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
10
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
11
Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center, University of Southern California, Los Angeles, CA 90089, USA.
12
GPCR Consortium, San Marcos, CA 92078, USA.
13
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bryan_roth@med.unc.edu.
14
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center, University of Southern California, Los Angeles, CA 90089, USA; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: stevens@shanghaitech.edu.cn.
15
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: liuzhj@shanghaitech.edu.cn.

Abstract

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

KEYWORDS:

GPCR; crystal structures; ergotamine; polypharmacology; ritanserin; selectivity; serotonin 2C receptor

PMID:
29398112
DOI:
10.1016/j.cell.2018.01.001

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