1. Academic Validation
  2. Ligand recognition and biased agonism of the D1 dopamine receptor

Ligand recognition and biased agonism of the D1 dopamine receptor

  • Nat Commun. 2022 Jun 8;13(1):3186. doi: 10.1038/s41467-022-30929-w.
Xiao Teng 1 2 Sijia Chen 2 3 Yingying Nie 2 Peng Xiao 4 Xiao Yu 5 Zhenhua Shao 6 Sanduo Zheng 7 8 9
Affiliations

Affiliations

  • 1 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 2 National Institute of Biological Sciences, Beijing, China.
  • 3 Graduate School of Peking Union Medical College, Beijing, 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, China.
  • 5 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, China.
  • 6 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 7 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. [email protected].
  • 8 National Institute of Biological Sciences, Beijing, China. [email protected].
  • 9 Graduate School of Peking Union Medical College, Beijing, China. [email protected].
Abstract

Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 Dopamine Receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.

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