9wt2 | pdb_00009wt2
Cryo-EM structure of Pi-free G6PT1 treated with GlcN6P
Structural highlights
DiseaseG6PT1_HUMAN Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionG6PT1_HUMAN Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction (PubMed:33964207). Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels.[1] [2] [3] Publication Abstract from PubMedGlucose-6-phosphate transporter 1 (G6PT1) is essential for systemic glucose homeostasis, and its deficiency causes glycogen storage disease type 1b (GSD1b). G6PT1 functions as a sugar-phosphate/inorganic phosphate (Pi) antiporter, orchestrating G6P transport into the endoplasmic reticulum lumen driven by a Pi gradient. Despite its physiological significance, the molecular mechanisms underlying substrate recognition and antiport activity remain poorly characterized. Here, we present cryo-electron microscopy structures of human G6PT1 in apo, Pi-bound, and GlcN6P-bound (a G6P analogue) states, all captured in cytosol-open conformations. Combined with molecular docking and functional assays, these structures elucidate the molecular basis for Pi and G6P recognition in G6PT1. Comparative analysis reveals that Pi binding triggers an interdomain salt bridge formation, resulting in a thicker luminal gate and a more compact central cavity for G6P binding. In addition to the monomer, we identify a dimeric assembly of G6PT1. Mutating key residues at the dimer interface impairs transport activity, suggesting a regulatory role for oligomerization. Our findings thus provide a mechanistic framework for understanding G6PT1 working mechanism and its pathological dysregulation in GSD1b. Structures of human glucose-6-phosphate transporter reveal reciprocal antiport mechanism driving glucose-6-phosphate and inorganic phosphate exchange.,Wang Q, Guo N, Du Y, Liu J, Ai W, Yang F, Zhu Y, Zhao Y, Wu D, Liu L, Yao X, Gao S Nat Commun. 2025 Dec 11;16(1):11441. doi: 10.1038/s41467-025-66386-4. PMID:41381426[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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