6e07 | pdb_00006e07

Crystal structure of Canton G6PD in complex with structural NADP

spinqualitylabelsall models 6e07, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6e07 is a 8 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 5vg5. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: GOL, NAP, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease G6PD_HUMAN Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:305900. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity. Function G6PD_HUMAN Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. Publication Abstract from PubMed 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. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator.,Hwang S, Mruk K, Rahighi S, Raub AG, Chen CH, Dorn LE, Horikoshi N, Wakatsuki S, Chen JK, Mochly-Rosen D Nat Commun. 2018 Oct 2;9(1):4045. doi: 10.1038/s41467-018-06447-z. PMID:30279493 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glucose 6-phosphate dehydrogenase

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