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Molecular basis of ligand recognition and activation of the human succinate receptor SUCR1

Cell Research volume 34, pages 594–596 (2024)Cite this article

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Dear Editor,

Succinic acid, once considered merely a tricarboxylic acid cycle intermediate,1 has been recognized for its significant role in influencing mitochondrial reactive oxygen species homeostasis.2 This is largely mediated through the G protein-coupled succinate receptor (SUCR1, also known as GPR91), which has emerged as a vital link connecting metabolic status to a myriad of physiological and pathological processes. SUCR1 is intricately involved in the regulation of blood pressure,3 angiogenesis,4 inflammation,5 and has been implicated in the pathogenesis of liver fibrosis,6 hypertension, and rheumatic arthritis.6 These multifaceted roles highlight the receptor’s potential as a promising therapeutic target for a wide spectrum of diseases. However, the molecular mechanisms underlying SUCR1’s activation by various ligands and its subsequent interaction with the inhibitory G protein (Gi) have remained elusive, hindering our comprehensive understanding of its broad physiological significance and therapeutic potential.

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Fig. 1: Molecular mechanisms underlying ligand recognition and activation of SUCR1 receptor.

Data availability

The cryo-EM density maps and corresponding atomic coordinates for the SUCR1–Gi complexes bound to succinic acid, maleic acid, and compound 31 have been deposited in the Electron Microscopy Data Bank (EMDB) and the Protein Data Bank (PDB), respectively, with the following accession codes: EMD-39374 and 8YKW for the SUCR1–Gi complex bound to succinic acid; EMD-39375 and 8YKX for the SUCR1–Gi complex bound to maleic acid; EMD-39373 and 8YKV for the SUCR1–Gi complex bound to compound 31.

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Acknowledgements

This work was supported by grants from CAS Strategic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to H.E.X.); Shanghai Municipal Science and Technology Major Project (H.E.X.); the National Natural Science Foundation of China (32130022, 82121005); the Lingang Laboratory (LG-GG-202204-01 to H.E.X.); the National Key R&D Program of China (2022YFC2703105 to H.E.X.). The cryo-EM data were collected at the Shanghai Advanced Electron Microscope Center, Shanghai Institute of Material Medica, Chinese Academy of Sciences. We thank Qingning Yuan, Kai Wu, Wen Hu, Shuai Li and Shufeng Zhang at the Shanghai Advanced Electron Microscope Center, Shanghai Institute of Material Medica, for providing technical support and assistance during data collection.

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Author notes

  1. These authors contributed equally: Changyao Li, Heng Liu, Jingru Li.

Authors and Affiliations

  1. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Changyao Li, Heng Liu, Xinheng He & H. Eric Xu

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

    Changyao Li & H. Eric Xu

  3. Lingang Laboratory, Shanghai, China

    Changyao Li & H. Eric Xu

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Jingru Li & H. Eric Xu

  5. University of Chinese Academy of Sciences, Beijing, China

    Xinheng He & H. Eric Xu

  6. School of Pharmacy, Fudan University, Shanghai, China

    Haoran Zhu & Wei Fu

Authors
  1. Changyao Li
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  2. Heng Liu
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  3. Jingru Li
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  4. Xinheng He
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  5. Haoran Zhu
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  6. Wei Fu
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  7. H. Eric Xu
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Contributions

H.E.X. initiated the project. C.L. designed and screened the expression constructs of SUCR1, prepared protein samples of succinic acid–SUCR1–Gi complex, maleic acid–SUCR1–Gi complex, and compound 31–SUCR1–Gi complex for cryo-EM data collection, participated in cryo-EM grid inspection, and executed the functional studies. H.L. performed cryo-EM grid preparation, data acquisition, structure determination and model building, and prepared the draft of the manuscript and figures. J.L. performed cell-based functional assay and participated in figure preparation. X.H. performed molecular dynamics simulations to validate ligand binding pose in SCUR1. H.Z. synthesized the compound 31 for structural study under the guidance of W.F. H.E.X. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Wei Fu or H. Eric Xu.

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The authors declare no competing interests.

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Li, C., Liu, H., Li, J. et al. Molecular basis of ligand recognition and activation of the human succinate receptor SUCR1. Cell Res 34, 594–596 (2024). https://doi.org/10.1038/s41422-024-00984-7

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  • DOI: https://doi.org/10.1038/s41422-024-00984-7

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