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Molecular activation and G protein coupling selectivity of human succinate receptor SUCR1

Cell Research (2024)Cite this article

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Dear Editor,

Succinate (SA) is a classic intermediate metabolite of the TCA cycle and is produced in mitochondria under normal physiological conditions.1 SA accumulates within cells and is secreted into the extracellular space, engaging in metabolic regulation and inflammatory response during conditions such as hypoxia, ischemia-reperfusion, and pro-inflammatory processes.2 Excess SA functions as a paracrine signal through its extracellular G protein-coupled receptor, SUCR1,3 which senses extracellular metabolic stress signals and regulates energy homeostasis.4 SUCR1 couples to Gi and Gq signaling pathways,5 resulting in physiological effects closely tied to human health and diseases such as hypertension, diabetes, inflammation, atherosclerosis, sepsis, immune response, cancer, asthma, and adiposity.3,6,7,8,9,10 Therefore, it is of great interest as a drug target. While the crystal structure of antagonist-bound rat SUCR1 complex has been resolved to clarify the inactivation mechanism of the receptor,11 a comprehensive understanding of the detailed molecular activation mechanism triggered by SA sensation is impeded by the lack of experimental active-state SUCR1 structures.

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Fig. 1: Structure basis of SUCR1 activation and G protein selectivity.

Data availability

The cryo-EM density maps have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under accession numbers EMD-36486 and 8JPP for SA–SUCR1–miniGs/q complex; and EMD-36484 and 8JPN for ESA–SUCR1–Gi complex.

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Acknowledgements

We acknowledge support from the National Natural Science Foundation of China (22121003, 22337006, 32027901 and 21927814), the National Key R&D Program of China (2019YFA0904201, 2023YFA0916300, 2021YFA0910202 and 2022YFA1304701), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB37040203) and the CAS Project for Young Scientists in Basic Research (YSBR-015 and YSBR-072-6). We thank J. Liu, N. Chen, S. Hu, L. Jiang, and Z. Fan from Insect Cell Expression Core and P. Si and X. Liu from Mammalian Cell Expression Core for Biomass production. The cryo-EM data were collected at the Bio-Electron Microscopy Facility of ShanghaiTech University with the assistance from L. Wang, D. Liu, Q. Sun, and Z. Zhang. This research also got support from Protein Purification Core, Cloning and Assays Cores of iHuman Institute.

Author information

Author notes

  1. These authors contributed equally: Tianxin Wang, Wenqin Tang, Xiaolei Zhu, Zhenyu Lv, Jiayan Chen, Yongze Li.

Authors and Affiliations

  1. iHuman Institute, ShanghaiTech University, Shanghai, China

    Tianxin Wang, Jiayan Chen, Haoyu Lv & Jiangyun Wang

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Tianxin Wang, Jiayan Chen & Haoyu Lv

  3. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Wenqin Tang, Xiaolei Zhu, Zhenyu Lv, Yongze Li, Xiaoyu Sun, Quanchang Gu, Fahui Li & Jiangyun Wang

  4. School of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Wenqin Tang, Xiaolei Zhu, Xiaoyu Sun, Quanchang Gu, Fahui Li & Jiangyun Wang

  5. Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, Beijing, China

    Wenqin Tang, Xiaolei Zhu, Zhenyu Lv, Yongze Li, Xiaoyu Sun, Quanchang Gu, Fahui Li & Jiangyun Wang

Authors
  1. Tianxin Wang
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  7. Xiaoyu Sun
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  11. Jiangyun Wang
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Contributions

J.W. organized the project. F.L., W.T., and X.S. guided all the structural analysis. F.L. designed all the mutants for functional analysis. T.W., J.C., Y.L., H.L., and Q.G. developed the SUCR1 constructs and optimized protein expression. T.W. and J.C. performed protein expression, prepared samples for cryo-EM grids, and collected the cryo-EM data. W.T. performed cryo-EM map calculation, model building, structure refinement, and MD simulations. Z.L. and X.Z. performed the functional assay. J.W. and F.L. wrote the manuscript. All the authors have read and commented on the manuscript.

Corresponding authors

Correspondence to Fahui Li or Jiangyun Wang.

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The authors declare no competing interests.

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Wang, T., Tang, W., Zhu, X. et al. Molecular activation and G protein coupling selectivity of human succinate receptor SUCR1. Cell Res (2024). https://doi.org/10.1038/s41422-024-00968-7

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  • DOI: https://doi.org/10.1038/s41422-024-00968-7

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