9j7v | pdb_00009j7v

Human G6PC1 in apo state

Structural highlights

9j7v 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 3.3Å
Ligands:	POV
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

G6PC1_HUMAN Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia. The disease is caused by variants affecting the gene represented in this entry.

Function

G6PC1_HUMAN Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The glucose-6-phosphatase (G6Pase) is an integral membrane protein that catalyzes the hydrolysis of glucose-6-phosphate (G6P) in the endoplasmic reticulum lumen and plays a vital role in glucose homeostasis. Dysregulation or genetic mutations of G6Pase are associated with diabetes and glycogen storage disease 1a (GSD-1a). Studies have characterized the biophysical and biochemical properties of G6Pase; however, the structure and substrate recognition mechanism of G6Pase remain unclear. Here, we present two cryo-EM structures of the 40-kDa human G6Pase: a wild-type apo form and a mutant G6Pase-H176A with G6P bound, elucidating the structural basis for substrate recognition and hydrolysis. G6Pase comprises nine transmembrane helices and possesses a large catalytic pocket facing the lumen. Unexpectedly, G6P binding induces substantial conformational rearrangements in the catalytic pocket, which facilitate the binding of the sugar moiety. In conjunction with functional analyses, this study provides critical insights into the structure, substrate recognition, catalytic mechanism, and pathology of G6Pase.

Structural insights into glucose-6-phosphate recognition and hydrolysis by human G6PC1.,Xia Z, Liu C, Wu D, Chen H, Zhao J, Jiang D Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2418316122. doi: , 10.1073/pnas.2418316122. Epub 2025 Jan 23. PMID:39847333^[6]

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

References

↑ Weston BW, Lin JL, Muenzer J, Cameron HS, Arnold RR, Seydewitz HH, Mayatepek E, Van Schaftingen E, Veiga-da-Cunha M, Matern D, Chen YT. Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype. Pediatr Res. 2000 Sep;48(3):329-34. PMID:10960498 doi:10.1203/00006450-200009000-00011
↑ Ghosh A, Shieh JJ, Pan CJ, Sun MS, Chou JY. The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis. J Biol Chem. 2002 Sep 6;277(36):32837-42. PMID:12093795 doi:10.1074/jbc.M201853200
↑ Angaroni CJ, de Kremer RD, Argaraña CE, Paschini-Capra AE, Giner-Ayala AN, Pezza RJ, Pan CJ, Chou JY. Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase mutations affecting protein stability. Mol Genet Metab. 2004 Nov;83(3):276-9. PMID:15542400 doi:10.1016/j.ymgme.2004.06.010
↑ Parvari R, Lei KJ, Bashan N, Hershkovitz E, Korman SH, Barash V, Lerman-Sagie T, Mandel H, Chou JY, Moses SW. Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies. Am J Med Genet. 1997 Oct 31;72(3):286-90. PMID:9332655 doi:<286::aid-ajmg6>3.0.co;2-p 10.1002/(sici)1096-8628(19971031)72:3<286::aid-ajmg6>3.0.co;2-p
↑ Pan CJ, Lei KJ, Annabi B, Hemrika W, Chou JY. Transmembrane topology of glucose-6-phosphatase. J Biol Chem. 1998 Mar 13;273(11):6144-8. PMID:9497333 doi:10.1074/jbc.273.11.6144
↑ Xia Z, Liu C, Wu D, Chen H, Zhao J, Jiang D. Structural insights into glucose-6-phosphate recognition and hydrolysis by human G6PC1. Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2418316122. PMID:39847333 doi:10.1073/pnas.2418316122

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Weston BW, Lin JL, Muenzer J, Cameron HS, Arnold RR, Seydewitz HH, Mayatepek E, Van Schaftingen E, Veiga-da-Cunha M, Matern D, Chen YT. Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype. Pediatr Res. 2000 Sep;48(3):329-34. PMID:10960498 doi:10.1203/00006450-200009000-00011

[2] Ghosh A, Shieh JJ, Pan CJ, Sun MS, Chou JY. The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis. J Biol Chem. 2002 Sep 6;277(36):32837-42. PMID:12093795 doi:10.1074/jbc.M201853200

[3] Angaroni CJ, de Kremer RD, Argaraña CE, Paschini-Capra AE, Giner-Ayala AN, Pezza RJ, Pan CJ, Chou JY. Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase mutations affecting protein stability. Mol Genet Metab. 2004 Nov;83(3):276-9. PMID:15542400 doi:10.1016/j.ymgme.2004.06.010

[4] Parvari R, Lei KJ, Bashan N, Hershkovitz E, Korman SH, Barash V, Lerman-Sagie T, Mandel H, Chou JY, Moses SW. Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies. Am J Med Genet. 1997 Oct 31;72(3):286-90. PMID:9332655 doi:<286::aid-ajmg6>3.0.co;2-p 10.1002/(sici)1096-8628(19971031)72:3<286::aid-ajmg6>3.0.co;2-p

[5] Pan CJ, Lei KJ, Annabi B, Hemrika W, Chou JY. Transmembrane topology of glucose-6-phosphatase. J Biol Chem. 1998 Mar 13;273(11):6144-8. PMID:9497333 doi:10.1074/jbc.273.11.6144

[6] Xia Z, Liu C, Wu D, Chen H, Zhao J, Jiang D. Structural insights into glucose-6-phosphate recognition and hydrolysis by human G6PC1. Proc Natl Acad Sci U S A. 2025 Jan 28;122(4):e2418316122. PMID:39847333 doi:10.1073/pnas.2418316122

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9j7v | pdb_00009j7v

Human G6PC1 in apo state

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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