2. Academic Validation
  3. Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes

Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes

  • Cell. 2021 Feb 18;184(4):943-956.e18. doi: 10.1016/j.cell.2021.01.028.
Peng Xiao 1,  Wei Yan 2,  Lu Gou 3,  Ya-Ni Zhong 4,  Liangliang Kong 5,  Chao Wu 2,  Xin Wen 4,  Yuan Yuan 2,  Sheng Cao 6,  Changxiu Qu 4,  Xin Yang 2,  Chuan-Cheng Yang 4,  Anjie Xia 2,  Zhenquan Hu 7,  Qianqian Zhang 8,  Yong-Hao He 9,  Dao-Lai Zhang 10,  Chao Zhang 11,  Gui-Hua Hou 11,  Huanxiang Liu 8,  Lizhe Zhu 7,  Ping Fu 2,  Shengyong Yang 2,  Daniel M Rosenbaum 12,  Jin-Peng Sun 13,  Yang Du 14,  Lei Zhang 15,  Xiao Yu 16,  Zhenhua Shao 17
Affiliations

Affiliations

  • 1 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
  • 4 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 5 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
  • 6 School of Life and Health Sciences, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.
  • 7 Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.
  • 8 School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 9 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China.
  • 10 School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China.
  • 11 Biomedical Isotope Research Center, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 12 Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 13 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: [email protected].
  • 14 School of Life and Health Sciences, Kobilka Institute of Innovative Drug Discovery, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China. Electronic address: [email protected].
  • 15 MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: [email protected].
  • 16 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 17 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
PMID: 33571432 DOI: 10.1016/j.cell.2021.01.028
Abstract

Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.

Keywords

DRD1-Gs complex; allosteric regulation; catecholamine; ccryo-EM; dopamine receptor; noncatechol; positive allosteric modulator; structure.

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