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Exploring the constitutive activation mechanism of the class A orphan GPR20

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

GPR20, an orphan G protein-coupled receptor (GPCR), shows significant expression in intestinal tissue and represents a potential therapeutic target to treat gastrointestinal stromal tumors. GPR20 performs high constitutive activity when coupling with Gi. Despite the pharmacological importance of GPCR constitutive activation, determining the mechanism has long remained unclear. In this study, we explored the constitutive activation mechanism of GPR20 through large-scale unbiased molecular dynamics simulations. Our results unveil the allosteric nature of constitutively activated GPCR signal transduction involving extracellular and intracellular domains. Moreover, the constitutively active state of the GPR20 requires both the N-terminal cap and Gi protein. The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift. Together with the previous study, this study enhances our knowledge of the self-activation mechanism of the orphan receptor, facilitates the drug discovery efforts that target GPR20.

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Fig. 1: GPR20 is coupled with the Gi protein.
Fig. 2: Cα RMSF analysis and extracellular conformations.
Fig. 3: Conformational changes in GPR20 activation pathways.
Fig. 4: Dynamic cross-correlation maps of four systems.
Fig. 5: Key residues linking ligand-binding pocket to G protein regions.
Fig. 6: Three R3.50–D7.49 states and FEL profiles of R1483.50 and D2937.49 torsions across systems.
Fig. 7: Intracellular conformations and SASA values.

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Acknowledgements

This study was supported by grants from the National Key R&D Program of China (No. 2023YFC3404700) and the National Natural Science Foundation of China (No. 22077082).

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Author notes

  1. These authors contributed equally: Ming-yang Zhang, Jian-yang Ao

Authors and Affiliations

  1. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China

    Ming-yang Zhang, Ning Liu & Shao-yong Lu

  2. Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ming-yang Zhang & Shao-yong Lu

  3. Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Jian-yang Ao

  4. Institute of Hepatobiliary and Pancreatic Surgery, Tongji University School of Medicine, Shanghai, 200120, China

    Jian-yang Ao

  5. Department of Cardiology, Changzheng Hospital, Affiliated to Naval Medical University, Shanghai, 200003, China

    Ting Chen

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  1. Ming-yang Zhang
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Contributions

SYL and TC conceived and designed the experiments; MYZ performed the experiments; MYZ, JYA and NL analyzed the data; MYZ wrote the original manuscript; SYL and TC reviewed and edited the manuscript; SYL and TC contributed reagents/materials/analysis tools.

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Correspondence to Ting Chen or Shao-yong Lu.

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Zhang, My., Ao, Jy., Liu, N. et al. Exploring the constitutive activation mechanism of the class A orphan GPR20. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01385-7

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