2. Academic Validation
  3. Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT

Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT

  • Nat Commun. 2025 Oct 24;16(1):9420. doi: 10.1038/s41467-025-64464-1.
Zhanyi Xia # 1 2,  Yaqi Wang # 3,  Di Wu # 1 2,  Cheng Chi # 4,  Chen Li 3,  Ligong Chen 5,  Daohua Jiang 6 7
Affiliations

Affiliations

  • 1 Beijing National Laboratory for Condensed Matter Physics, Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
  • 2 School of Physical Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 3 State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China.
  • 4 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, China.
  • 5 State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China. ligongchen@tsinghua.edu.cn.
  • 6 Beijing National Laboratory for Condensed Matter Physics, Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.
  • 7 School of Physical Sciences, University of Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.
  • # Contributed equally.
PMID: 41136424 DOI: 10.1038/s41467-025-64464-1
Abstract

The human glucose-6-phosphate transporter (G6PT) moves glucose-6-phosphate (G6P) into the lumen of endoplasmic reticulum, playing a vital role in glucose homeostasis. Dysregulation of G6PT causes glycogen storage disease 1b. Despite its functional importance, the structure, G6P recognition, and inhibition mechanism of G6PT remain unclear. Here, we report the cryo-EM structures of human G6PT in apo, G6P-bound, and the specific inhibitor chlorogenic acid (CHA)-bound forms, elucidating the structural basis for G6PT transport and inhibition. The G6P pocket comprises subsite A for phosphate and subsite B for glucose. The CHA occupies the G6P site and locks G6PT in a partly-occluded state. Functional assays demonstrate that G6PT activity is enhanced by co-expression of glucose-6-phosphatase (G6PC), but G6PT does not form a complex with G6PC. Together, this study provides a solid foundation for understanding the structure‒function relationships and pathology of G6PT and sheds light on the future development of potential therapeutics targeting G6PT.

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