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|1pgn, resolution 2.30Å ()|
|Related:||2pgd, 1pgo, 1pgp, 1pgq|
CRYSTALLOGRAPHIC STUDY OF COENZYME, COENZYME ANALOGUE AND SUBSTRATE BINDING IN 6-PHOSPHOGLUCONATE DEHYDROGENASE: IMPLICATIONS FOR NADP SPECIFICITY AND THE ENZYME MECHANISM
BACKGROUND: The nicotinamide adenine dinucleotide phosphate (NADP)-dependent oxidative decarboxylase, 6-phosphogluconate dehydrogenase, is a major source of reduced coenzyme for synthesis. Enzymes later in the pentose phosphate pathway convert the reaction product, ribulose 5-phosphate, to ribose 5-phosphate. Crystallographic study of complexes with coenzyme and substrate explain the NADP dependence which determines the enzyme's metabolic role and support the proposed general base-general acid mechanism. RESULTS: The refined structures of binary coenzyme/analogue complexes show that Arg33 is ordered by binding the 2'-phosphate, and provides one face of the adenine site. The nicotinamide, while less tightly bound, is more extended when reduced than when oxidized. All substrate binding residues are conserved; the 3-hydroxyl of 6-phosphogluconate is hydrogen bonded to N zeta of Lys183 and the 3-hydrogen points towards the oxidized nicotinamide. The 6-phosphate replaces a tightly bound sulphate in the apo-enzyme. CONCLUSIONS: NADP specificity is achieved primarily by Arg33 which binds the 2'-phosphate but, in its absence, obscures the adenine pocket. The bound oxidized nicotinamide is syn; hydride transfer from bound substrate to the nicotinamide si- face is achieved with a small movement of the nicotinamide nucleotide. Lys183 may act as general base. A water bound to Gly130 in the coenzyme domain is the most likely acid required in decarboxylation. The dihydronicotinamide ring of NADPH competes for ligands with the 1-carboxyl of 6-phosphogluconate.
Crystallographic study of coenzyme, coenzyme analogue and substrate binding in 6-phosphogluconate dehydrogenase: implications for NADP specificity and the enzyme mechanism., Adams MJ, Ellis GH, Gover S, Naylor CE, Phillips C, Structure. 1994 Jul 15;2(7):651-68. PMID:7922042
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Adams MJ, Ellis GH, Gover S, Naylor CE, Phillips C. Crystallographic study of coenzyme, coenzyme analogue and substrate binding in 6-phosphogluconate dehydrogenase: implications for NADP specificity and the enzyme mechanism. Structure. 1994 Jul 15;2(7):651-68. PMID:7922042
- Britton KL, Asano Y, Rice DW. Crystal structure and active site location of N-(1-D-carboxylethyl)-L-norvaline dehydrogenase. Nat Struct Biol. 1998 Jul;5(7):593-601. PMID:9665174 doi:10.1038/854