Structural insights into the human D1 and D2 dopamine receptor signaling complexes

Youwen Zhuang; Peiyu Xu; Chunyou Mao; Lei Wang; Brian Krumm; X Edward Zhou; Sijie Huang; Heng Liu; Xi Cheng; Xi-Ping Huang; Dan-Dan Shen; Tinghai Xu; Yong-Feng Liu; Yue Wang; Jia Guo; Yi Jiang; Hualiang Jiang; Karsten Melcher; Bryan L Roth; Yan Zhang; Cheng Zhang; H Eric Xu

doi:10.1016/j.cell.2021.01.027

Structural insights into the human D1 and D2 dopamine receptor signaling complexes

Cell. 2021 Feb 18;184(4):931-942.e18. doi: 10.1016/j.cell.2021.01.027. Epub 2021 Feb 10.

Authors

Youwen Zhuang¹, Peiyu Xu², Chunyou Mao³, Lei Wang⁴, Brian Krumm⁵, X Edward Zhou⁶, Sijie Huang⁷, Heng Liu⁴, Xi Cheng⁸, Xi-Ping Huang⁵, Dan-Dan Shen³, Tinghai Xu⁶, Yong-Feng Liu⁵, Yue Wang¹, Jia Guo¹, Yi Jiang¹, Hualiang Jiang⁸, Karsten Melcher⁶, Bryan L Roth⁹, Yan Zhang¹⁰, Cheng Zhang¹¹, H Eric Xu¹²

Affiliations

¹ 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; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
³ 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 and 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, China.
⁴ Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁵ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
⁶ Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
⁷ 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, Shanghai 201210, 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 at Chapel Hill, Chapel Hill, NC 27599-7365, USA. Electronic address: bryan_roth@med.unc.edu.
¹⁰ 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 and 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, China; Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China. Electronic address: zhang_yan@zju.edu.cn.
¹¹ Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: chengzh@pitt.edu.
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, Shanghai 201210, China. Electronic address: eric.xu@simm.ac.cn.

Abstract

The D1- and D2-dopamine receptors (D1R and D2R), which signal through G_s and G_i, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G_s and D2R-G_i signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.

Keywords: D1R; D2R; G protein selectivity; Parkinson’s disease; apomorphine; bromocriptine; cryo-EM; dopamine receptors; ligand selectivity; receptor activation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / analogs & derivatives
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
Amino Acid Sequence
Conserved Sequence
Cryoelectron Microscopy
Cyclic AMP / metabolism
GTP-Binding Proteins / metabolism
HEK293 Cells
Humans
Ligands
Models, Molecular
Mutant Proteins / chemistry
Mutant Proteins / metabolism
Receptors, Adrenergic, beta-2 / metabolism
Receptors, Dopamine D1 / chemistry*
Receptors, Dopamine D1 / metabolism*
Receptors, Dopamine D1 / ultrastructure
Receptors, Dopamine D2 / chemistry*
Receptors, Dopamine D2 / metabolism*
Receptors, Dopamine D2 / ultrastructure
Signal Transduction*
Structural Homology, Protein

Substances

Ligands
Mutant Proteins
Receptors, Adrenergic, beta-2
Receptors, Dopamine D1
Receptors, Dopamine D2
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
SK&F 83959
Cyclic AMP
GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding