1gth

From Proteopedia

Revision as of 14:13, 5 November 2007

DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND 5-IODOURACIL

Overview

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.

About this Structure

1GTH is a Single protein structure of sequence from Sus scrofa with SF4, FMN, FAD, NDP, IDH, IUR and URA as ligands. Active as Dihydropyrimidine dehydrogenase (NADP(+)), with EC number 1.3.1.2 Structure known Active Site: FA1. 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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