Structures of the human dopamine D3 receptor-Gi complexes

doi:10.1016/j.molcel.2021.01.003

. 2021 Mar 18;81(6):1147-1159.e4.

doi: 10.1016/j.molcel.2021.01.003. Epub 2021 Feb 5.

Structures of the human dopamine D3 receptor-G_i complexes

Peiyu Xu¹, Sijie Huang², Chunyou Mao³, Brian E Krumm⁴, X Edward Zhou⁵, Yangxia Tan², Xi-Ping Huang⁴, Yongfeng Liu⁴, Dan-Dan Shen³, Yi Jiang⁶, Xuekui Yu⁷, Hualiang Jiang⁸, Karsten Melcher⁵, Bryan L Roth⁹, Xi Cheng¹⁰, Yan Zhang¹¹, H Eric Xu¹²

Affiliations

¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
³ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA.
⁵ Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
⁶ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁷ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁹ Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA. Electronic address: bryan_roth@med.unc.edu.
¹⁰ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xicheng@simm.ac.cn.
¹¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China; Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, Zhejiang, China. Electronic address: zhang_yan@zju.edu.cn.
¹² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China. Electronic address: eric.xu@simm.ac.cn.

PMID: 33548201
DOI: 10.1016/j.molcel.2021.01.003

Free article

Structures of the human dopamine D3 receptor-G_i complexes

Peiyu Xu et al. Mol Cell. 2021.

Free article

. 2021 Mar 18;81(6):1147-1159.e4.

doi: 10.1016/j.molcel.2021.01.003. Epub 2021 Feb 5.

Authors

Affiliations

¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
³ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA.
⁵ Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
⁶ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁷ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁹ Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA. Electronic address: bryan_roth@med.unc.edu.
¹⁰ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xicheng@simm.ac.cn.
¹¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China; Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, Zhejiang, China. Electronic address: zhang_yan@zju.edu.cn.
¹² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China. Electronic address: eric.xu@simm.ac.cn.

PMID: 33548201
DOI: 10.1016/j.molcel.2021.01.003

Abstract

The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for G_i protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.

Keywords: D3R; G protein selectivity; GPCR; Parkinson’s disease; cryo-EM structure; dopamine receptor; dopamine receptor activation; ligand selectivity; pramipexole; signaling complex.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Structures of the human dopamine D3 receptor-G_i complexes

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Structures of the human dopamine D3 receptor-G_i complexes

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