Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

Youwen Zhuang^#^{1

2}, Brian Krumm^#³, Huibing Zhang^#^{4

5}, X Edward Zhou⁶, Yue Wang^{1

2}, Xi-Ping Huang³, Yongfeng Liu³, Xi Cheng⁷, Yi Jiang^{1

2}, Hualiang Jiang⁷, Cheng Zhang⁸, Wei Yi⁹, Bryan L Roth¹⁰, Yan Zhang^{11

12

13}, H Eric Xu^{14

15}

Affiliations

¹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA.
⁴ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
⁵ MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
⁶ Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand, Rapids, MI, USA.
⁷ 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.
⁸ Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁹ Key Laboratory of Molecular Target & Clinical Pharmacology, and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
¹⁰ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA. bryan_roth@med.unc.edu.
¹¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. zhang_yan@zju.edu.cn.
¹² MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. zhang_yan@zju.edu.cn.
¹³ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, 311121, China. zhang_yan@zju.edu.cn.
¹⁴ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Eric.Xu@simm.ac.cn.
¹⁵ University of Chinese Academy of Sciences, Beijing, 100049, China. Eric.Xu@simm.ac.cn.

^# Contributed equally.

PMID: 33750903
PMCID: PMC8089099
DOI: 10.1038/s41422-021-00482-0

Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

Youwen Zhuang et al. Cell Res. 2021 May.

. 2021 May;31(5):593-596.

doi: 10.1038/s41422-021-00482-0. Epub 2021 Mar 9.

Authors

Affiliations

¹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA.
⁴ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
⁵ MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
⁶ Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand, Rapids, MI, USA.
⁷ 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.
⁸ Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁹ Key Laboratory of Molecular Target & Clinical Pharmacology, and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
¹⁰ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7365, USA. bryan_roth@med.unc.edu.
¹¹ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. zhang_yan@zju.edu.cn.
¹² MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. zhang_yan@zju.edu.cn.
¹³ Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, 311121, China. zhang_yan@zju.edu.cn.
¹⁴ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Eric.Xu@simm.ac.cn.
¹⁵ University of Chinese Academy of Sciences, Beijing, 100049, China. Eric.Xu@simm.ac.cn.

^# Contributed equally.

PMID: 33750903
PMCID: PMC8089099
DOI: 10.1038/s41422-021-00482-0

No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Structures of DRD1–Gs complexes.**
a Chemical structures of ligands. b Cryo-EM maps and structures of the DRD1–dopamine–G_s complex and the DRD1–SKF81297–G_s complex, both in the presence of LY3154207. The maps are shown at 0.045 and 0.083 thresholds for DRD1–dopamine/LY3154207–G_s complex and DRD1–SKF81297/LY3154207–G_s complex, respectively. c The dopamine and SKF81297 OBPs. d Interactions of dopamine and SKF81297 with DRD1. e Superposition of DRD1–SKF81297–G_s structures with or without LY3154207. The structure without PAM (white); the structure with PAM (DRD1, pink; SKF81297, teal; LY3154207, light yellow; G_αs, salmon; G_β, cyan; G_γ, magenta). The hydrogen bond interactions are shown as black dashed line and yellow dashed line for DRD1–SKF81297 structure and DRD1–SKF81297/LY3154207 structure, respectively. f The binding mode of LY3154207 (left panel) and the conformational differences of the DRD1 allosteric binding site with or without LY3154207 (right panel). LY3154207 was removed in the right panel for better presentation of the alignment. g cAMP accumulation analysis of WT DRD1 and DRD1 mutants activated by dopamine. Data are presented as means ± SEM with a minimum of two technical replicates and n = 3 biological replicates. Greek letter delta (Δ) represents the difference between pEC50 values of the mutant DRD1 and the WT receptor (ΔpEC50) . h Comparison of dopamine and SKF81297 in cAMP accumulation assays with WT and mutant DRD1 in the presence or absence of 30 nM LY3154207. Data are presented as means ± SEM with a minimum of two technical replicates and n = 3 biological replicates. ΔpEC50 is for the comparison of the pEC50s of WT or each mutant in the presence of 30 nM LY3154207, with those in the absence of LY3154207.

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Comment in

Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential.
Sibley DR, Luderman KD, Free RB, Shi L. Sibley DR, et al. Signal Transduct Target Ther. 2021 May 22;6(1):205. doi: 10.1038/s41392-021-00630-3. Signal Transduct Target Ther. 2021. PMID: 34023856 Free PMC article. No abstract available.

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Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

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Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

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