1gth

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[[Image:1gth.gif|left|200px]]<br /><applet load="1gth" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1gth, resolution 2.25&Aring;" />
 
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'''DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND 5-IODOURACIL'''<br />
 
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==Overview==
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==DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX WITH NADPH AND 5-IODOURACIL==
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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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<StructureSection load='1gth' size='340' side='right'caption='[[1gth]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[1gth]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GTH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GTH FirstGlance]. <br>
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1GTH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=SF4:'>SF4</scene>, <scene name='pdbligand=FMN:'>FMN</scene>, <scene name='pdbligand=FAD:'>FAD</scene>, <scene name='pdbligand=NDP:'>NDP</scene>, <scene name='pdbligand=IDH:'>IDH</scene>, <scene name='pdbligand=IUR:'>IUR</scene> and <scene name='pdbligand=URA:'>URA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydropyrimidine_dehydrogenase_(NADP(+)) Dihydropyrimidine dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.2 1.3.1.2] Known structural/functional Site: <scene name='pdbsite=FA1:Ura+Binding+Site+For+Chain+D'>FA1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GTH OCA].
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=IDH:(5S)-5-IODODIHYDRO-2,4(1H,3H)-PYRIMIDINEDIONE'>IDH</scene>, <scene name='pdbligand=IUR:5-IODOURACIL'>IUR</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=URA:URACIL'>URA</scene></td></tr>
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==Reference==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gth FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gth OCA], [https://pdbe.org/1gth PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gth RCSB], [https://www.ebi.ac.uk/pdbsum/1gth PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gth ProSAT]</span></td></tr>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11796730 11796730]
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</table>
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[[Category: Dihydropyrimidine dehydrogenase (NADP(+))]]
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== Function ==
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[[Category: Single protein]]
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[https://www.uniprot.org/uniprot/DPYD_PIG DPYD_PIG] Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine.<ref>PMID:9860876</ref> <ref>PMID:20831907</ref> <ref>PMID:11179210</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gt/1gth_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1gth ConSurf].
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<div style="clear:both"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
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[[Category: Dobritzsch, D.]]
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[[Category: Dobritzsch D]]
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[[Category: Lindqvist, Y.]]
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[[Category: Lindqvist Y]]
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[[Category: Ricagno, S.]]
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[[Category: Ricagno S]]
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[[Category: Schnackerz, K D.]]
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[[Category: Schnackerz KD]]
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[[Category: Schneider, G.]]
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[[Category: Schneider G]]
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[[Category: FAD]]
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[[Category: FMN]]
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[[Category: IDH]]
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[[Category: IUR]]
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[[Category: NDP]]
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[[Category: SF4]]
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[[Category: URA]]
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[[Category: 5-fluorouracil degradation]]
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[[Category: electron transfer]]
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[[Category: flavin]]
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[[Category: iron-sulfur clusters]]
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[[Category: oxidoreductase]]
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[[Category: pyrimidine catabolism]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:53:47 2008''
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Current revision

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

PDB ID 1gth

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