1gt8

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{{STRUCTURE_1gt8| PDB=1gt8 | SCENE= }}
{{STRUCTURE_1gt8| PDB=1gt8 | SCENE= }}
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'''DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND URACIL-4-ACETIC ACID'''
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===DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND URACIL-4-ACETIC ACID===
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==Overview==
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Dihydroprymidine dehydrogenase catalyzes the first and rate-limiting step in pyrimidine degradation by converting pyrimidines to the corresponding 5,6- dihydro compounds. The three-dimensional structures of a binary complex with the inhibitor 5-iodouracil and two ternary complexes with NADPH and the inhibitors 5-iodouracil and uracil-4-acetic acid were determined by x-ray crystallography. In the ternary complexes, NADPH is bound in a catalytically competent fashion, with the nicotinamide ring in a position suitable for hydride transfer to FAD. The structures provide a complete picture of the electron transfer chain from NADPH to the substrate, 5-iodouracil, spanning a distance of 56 A and involving FAD, four [Fe-S] clusters, and FMN as cofactors. The crystallographic analysis further reveals that pyrimidine binding triggers a conformational change of a flexible active-site loop in the alpha/beta-barrel domain, resulting in placement of a catalytically crucial cysteine close to the bound substrate. Loop closure requires physiological pH, which is also necessary for correct binding of NADPH. Binding of the voluminous competitive inhibitor uracil-4-acetic acid prevents loop closure due to steric hindrance. The three-dimensional structure of the ternary complex enzyme-NADPH-5-iodouracil supports the proposal that this compound acts as a mechanism-based inhibitor, covalently modifying the active-site residue Cys-671, resulting in S-(hexahydro-2,4-dioxo-5-pyrimidinyl)cysteine.
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{{ABSTRACT_PUBMED_11796730}}
==About this Structure==
==About this Structure==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Pyrimidine catabolism]]
[[Category: Pyrimidine catabolism]]
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Revision as of 03:02, 1 July 2008

Image:1gt8.png

Template:STRUCTURE 1gt8

DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND URACIL-4-ACETIC ACID

Template:ABSTRACT PUBMED 11796730

About this Structure

1GT8 is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.

Reference

Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer., Dobritzsch D, Ricagno S, Schneider G, Schnackerz KD, Lindqvist Y, J Biol Chem. 2002 Apr 12;277(15):13155-66. Epub 2002 Jan 16. PMID:11796730

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