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Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

The global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function variants to protection against obesity and type 2 diabetes. However, structural insights have remained elusive due to GPR75’s inherent expression and stabilization challenges. Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states, achieved through advanced stabilization techniques including NanoBiT and molecular glue approaches. Our structures reveal unique architectural features: a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands. GPR75 assumes active-like conformation in both apo and G protein complexed structures through unique molecular switches—the canonical DRY motif is replaced by HRL, abolishing the ionic lock, while a distinctive Lys134-Asp210 salt bridge stabilizes the active conformation without ligand binding. This dramatic structural divergence from conventional GPCRs necessitates alternative therapeutic strategies targeting allosteric sites or protein-protein interactions rather than orthosteric pockets. Our findings establish a crucial structural framework for developing next-generation anti-obesity therapeutics.

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Fig. 1: Cryo-EM structures of GPR75 and GPR75-Gq complex.
Fig. 2: Unique feature of GPR75.
Fig. 3: The active structure of GPR75.
Fig. 4: G protein coupling of GPR75.

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Data availability

The atomic coordinates of complex, GPR75-Gq complex, and Apo-GPR75BRIL are deposited at Protein Data Bank under access codes 9XQC, and 9XQN, respectively. Cryo-EM density maps of GPR75-Gq complex, and Apo-GPR75BRIL complex are deposited at Electron Microscopy Data Bank under access numbers EMD-67110, and EMD-67119, respectively.

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Acknowledgements

The cryo-EM data were collected at the Shanghai Advanced Center for Electron Microscopy, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The National Key R&D Program of China (2022YFA1302900 to WCY; 2022YFC2703105 to HEX); the National Natural Science Foundation of China (32301016 to CRW, 32130022, 82495184, 82121005 to HEX, 82404881 to QNY); National Key R&D Program “Strategic Scientific and Technological Innovation Cooperation” Key Project (2022YFE0203600) released by the Ministry of Science and Technology; CAS Strategic Priority Research Program (XDB37030103 to HEX); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to HEX); Shanghai Municipal Science and Technology Major Project (HEX); Supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB0830000 to HEX.

We thank Claude 4.5 (Anthropic) for assistance with manuscript editing and language refinement.

Author information

Author notes

  1. These authors contributed equally: Zi-ning Zhu, Chong-zhao You, Qing-ning Yuan

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Zi-ning Zhu, Wen Hu, Kai Wang, You-wei Xu & H. Eric Xu

  2. Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zi-ning Zhu, Qing-ning Yuan, Zong-yue Gu & Wan-chao Yin

  3. Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Chong-zhao You

  4. Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Qing-ning Yuan, Jiu-yin Xu, H. Eric Xu & Can-rong Wu

  5. BioFront Therapeutics, Beijing, 100089, China

    Zheng Huang, Miao Liu & Bei Shan

  6. Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    James Jiqi Wang

  7. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Wan-chao Yin

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Contributions

ZNZ, CZY, and QNY contributed equally to this work. CZY expressed and purified the GPR75-Gq complexes and prepared cryo-EM samples. ZNZ expressed and purified the apo GPR75 complexes and prepared cryo-EM samples. QNY and WH collected cryo-EM data. QNY, CRW, and CZY performed cryo-EM data processing and image analysis. QNY and CRW built and refined the atomic models. JJW, JYX, ZYG, KW, WCY, and YWX provided experimental assistance and technical support. ZH, ML, and BS provided scientific advice and contributed to data analysis. HEX and CRW conceived and designed the project, supervised all aspects of the research, analyzed the data, and wrote the manuscript with input from all authors. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to H. Eric Xu or Can-rong Wu.

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Competing interests

ZH, ML, and BS are employed by BioFront Therapeutics. HEX is one of the Associate Editors of APS and was not involved in the peer review or the decision making of the article. The authors declare no other competing interests.

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Zhu, Zn., You, Cz., Yuan, Qn. et al. Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01720-6

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