6E07

Crystal structure of Canton G6PD in complex with structural NADP

Replaces:  5VG5

Summary for 6E07

• Entry DOI: 10.2210/pdb6e07/pdb
• Descriptor: Glucose-6-phosphate 1-dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: g6pd, nadp, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 483686.11

Authors

Rahighi, S.,Mochly-Rosen, D.,Wakatsuki, S. (deposition date: 2018-07-06, release date: 2018-07-25, Last modification date: 2023-10-11)

Primary citation

Hwang, S.,Mruk, K.,Rahighi, S.,Raub, A.G.,Chen, C.H.,Dorn, L.E.,Horikoshi, N.,Wakatsuki, S.,Chen, J.K.,Mochly-Rosen, D.
Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator.
Nat Commun, 9:4045-4045, 2018

PubMed Abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.

PubMed: 30279493
DOI: 10.1038/s41467-018-06447-z

Experimental method

X-RAY DIFFRACTION (2.6 Å)