7SNH

Structure of G6PD-D200N tetramer bound to NADP+

Summary for 7SNH

• Entry DOI: 10.2210/pdb7snh/pdb
• EMDB information: 25226
• Descriptor: Glucose-6-phosphate 1-dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (2 entities in total)
• Functional Keywords: apo protein, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 247562.26

Authors

Wei, X.,Marmorstein, R. (deposition date: 2021-10-28, release date: 2022-07-13, Last modification date: 2024-06-05)

Primary citation

Wei, X.,Kixmoeller, K.,Baltrusaitis, E.,Yang, X.,Marmorstein, R.
Allosteric role of a structural NADP + molecule in glucose-6-phosphate dehydrogenase activity.
Proc.Natl.Acad.Sci.USA, 119:e2119695119-e2119695119, 2022

PubMed Abstract: Human glucose-6-phosphate dehydrogenase (G6PD) is the main cellular source of NADPH, and thus plays a key role in maintaining reduced glutathione to protect cells from oxidative stress disorders such as hemolytic anemia. G6PD is a multimeric enzyme that uses the cofactors β-D-glucose 6-phosphate (G6P) and "catalytic" NADP (NADPc), as well as a "structural" NADP (NADPs) located ∼25 Å from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADPs in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADPs have not been evaluated. Here, we determined the high resolution cryo-electron microscopy structures of human wild-type G6PD in the absence of bound ligands and a catalytic G6PD-D200N mutant bound to NADPc and NADPs in the absence or presence of G6P. A comparison of these structures, together with previously reported structures, reveals that the unliganded human G6PD forms a mixture of dimers and tetramers with similar overall folds, and binding of NADPs induces a structural ordering of a C-terminal extension region and allosterically regulates G6P binding and catalysis. These studies have implications for understanding G6PD deficiencies and for therapy of G6PD-mediated disorders.

PubMed: 35858355
DOI: 10.1073/pnas.2119695119

Experimental method

ELECTRON MICROSCOPY (2.2 Å)