9kvv

From Proteopedia

Cryo-EM structure of human G6PT in complex with G6P

Structural highlights

9kvv is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

G6PT1_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.

Function

G6PT1_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 PubMed

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 structureâfunction relationships and pathology of G6PT and sheds light on the future development of potential therapeutics targeting G6PT.

Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT.,Xia Z, Wang Y, Wu D, Chi C, Li C, Chen L, Jiang D Nat Commun. 2025 Oct 24;16(1):9420. doi: 10.1038/s41467-025-64464-1. PMID:41136424^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hiraiwa H, Pan CJ, Lin B, Moses SW, Chou JY. Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b. J Biol Chem. 1999 Feb 26;274(9):5532-6. PMID:10026167 doi:10.1074/jbc.274.9.5532
↑ Pan CJ, Chen SY, Jun HS, Lin SR, Mansfield BC, Chou JY. SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphate antiporters. PLoS One. 2011;6(9):e23157. PMID:21949678 doi:10.1371/journal.pone.0023157
↑ Ng BG, Sosicka P, Fenaille F, Harroche A, Vuillaumier-Barrot S, Porterfield M, Xia ZJ, Wagner S, Bamshad MJ, Vergnes-Boiteux MC, Cholet S, Dalton S, Dell A, Dupré T, Fiore M, Haslam SM, Huguenin Y, Kumagai T, Kulik M, McGoogan K, Michot C, Nickerson DA, Pascreau T, Borgel D, Raymond K, Warad D, Flanagan-Steet H, Steet R, Tiemeyer M, Seta N, Bruneel A, Freeze HH. A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction. Am J Hum Genet. 2021 Jun 3;108(6):1040-1052. PMID:33964207 doi:10.1016/j.ajhg.2021.04.013
↑ Xia Z, Wang Y, Wu D, Chi C, Li C, Chen L, Jiang D. Structural basis for transport and inhibition of the human glucose-6-phosphate transporter G6PT. Nat Commun. 2025 Oct 24;16(1):9420. PMID:41136424 doi:10.1038/s41467-025-64464-1