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==DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL==
==DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL==
<StructureSection load='1gte' size='340' side='right' caption='[[1gte]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
<StructureSection load='1gte' size='340' side='right'caption='[[1gte]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1gte]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GTE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GTE FirstGlance]. <br>
<table><tr><td colspan='2'>[[1gte]] 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=1GTE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GTE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=IUR:5-IODOURACIL'>IUR</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1h7w|1h7w]], [[1h7x|1h7x]], [[1gt8|1gt8]], [[1gth|1gth]]</td></tr>
<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=IUR:5-IODOURACIL'>IUR</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gte FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gte OCA], [https://pdbe.org/1gte PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gte RCSB], [https://www.ebi.ac.uk/pdbsum/1gte PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gte ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gte FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gte OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1gte RCSB], [http://www.ebi.ac.uk/pdbsum/1gte PDBsum]</span></td></tr>
</table>
</table>
== Function ==
[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>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gt/1gte_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gt/1gte_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
</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/chain_selection.php?pdb_ID=2ata ConSurf].
</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=1gte ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.
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<ref>PMID:11796730</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Dobritzsch, D]]
[[Category: Dobritzsch D]]
[[Category: Lindqvist, Y]]
[[Category: Lindqvist Y]]
[[Category: Ricagno, S]]
[[Category: Ricagno S]]
[[Category: Schnackerz, K D]]
[[Category: Schnackerz KD]]
[[Category: Schneider, G]]
[[Category: Schneider G]]
[[Category: 5-fluorouracil degradation]]
[[Category: Electron transfer]]
[[Category: Flavin]]
[[Category: Iron-sulfur cluster]]
[[Category: Oxidoreductase]]
[[Category: Pyrimidine catabolism]]

Latest revision as of 14:24, 27 March 2024

DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACILDIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, BINARY COMPLEX WITH 5-IODOURACIL

Structural highlights

1gte is a 4 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.65Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DPYD_PIG Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine.[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

  1. ↑ Rosenbaum K, Jahnke K, Curti B, Hagen WR, Schnackerz KD, Vanoni MA. Porcine recombinant dihydropyrimidine dehydrogenase: comparison of the spectroscopic and catalytic properties of the wild-type and C671A mutant enzymes. Biochemistry. 1998 Dec 15;37(50):17598-609. PMID:9860876 doi:http://dx.doi.org/10.1021/bi9815997
  2. ↑ Lohkamp B, Voevodskaya N, Lindqvist Y, Dobritzsch D. Insights into the mechanism of dihydropyrimidine dehydrogenase from site-directed mutagenesis targeting the active site loop and redox cofactor coordination. Biochim Biophys Acta. 2010 Dec;1804(12):2198-206. doi:, 10.1016/j.bbapap.2010.08.014. Epub 2010 Sep 8. PMID:20831907 doi:http://dx.doi.org/10.1016/j.bbapap.2010.08.014
  3. ↑ Dobritzsch D, Schneider G, Schnackerz KD, Lindqvist Y. Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. EMBO J. 2001 Feb 15;20(4):650-60. PMID:11179210 doi:10.1093/emboj/20.4.650

1gte, resolution 1.65Å

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