2hqu

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[[Image:2hqu.jpg|left|200px]]
 
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{{Structure
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==Human dUTPase in complex with alpha,beta-iminodUTP and magnesium ion==
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|PDB= 2hqu |SIZE=350|CAPTION= <scene name='initialview01'>2hqu</scene>, resolution 2.20&Aring;
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<StructureSection load='2hqu' size='340' side='right'caption='[[2hqu]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene> and <scene name='pdbligand=DUP:2&#39;-DEOXYURIDINE 5&#39;-ALPHA,BETA-IMIDO-TRIPHOSPHATE'>DUP</scene>
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<table><tr><td colspan='2'>[[2hqu]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HQU FirstGlance]. <br>
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|ACTIVITY= [http://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23]
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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]] 2.2&#8491;</td></tr>
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|GENE= DUTN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DUP:2-DEOXYURIDINE+5-ALPHA,BETA-IMIDO-TRIPHOSPHATE'>DUP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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}}
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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=2hqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hqu OCA], [https://pdbe.org/2hqu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hqu RCSB], [https://www.ebi.ac.uk/pdbsum/2hqu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hqu ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</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/hq/2hqu_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=2hqu ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Human dUTPase, essential for DNA integrity, is an important survival factor for cancer cells. We determined the crystal structure of the enzyme:alpha,beta-imino-dUTP:Mg complex and performed equilibrium binding experiments in solution. Ordering of the C-terminus upon the active site induces close juxtaposition of the incoming nucleophile attacker water oxygen and the alpha-phosphorus of the substrate, decreasing their distance below the van der Waals limit. Complex interactions of the C-terminus with both substrate and product were observed via a specifically designed tryptophan sensor, suitable for further detailed kinetic and ligand binding studies. Results explain the key functional role of the C-terminus.
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'''Human dUTPase in complex with alpha,beta-iminodUTP and magnesium ion'''
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Active site closure facilitates juxtaposition of reactant atoms for initiation of catalysis by human dUTPase.,Varga B, Barabas O, Kovari J, Toth J, Hunyadi-Gulyas E, Klement E, Medzihradszky KF, Tolgyesi F, Fidy J, Vertessy BG FEBS Lett. 2007 Oct 2;581(24):4783-8. Epub 2007 Sep 12. PMID:17880943<ref>PMID:17880943</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2hqu" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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BACKGROUND. The essential enzyme dUTP pyrophosphatase (dUTPase) is exquisitely specific for dUTP and is critical for the fidelity of DNA replication and repair. dUTPase hydrolyzes dUTP to dUMP and pyrophosphate, simultaneously reducing dUTP levels and providing the dUMP for dTTP biosynthesis. A high cellular dTTP: dUTP ratio is essential to avoid uracil incorporation into DNA, which would lead to strand breaks and cell death. We report the first detailed atomic-resolution structure of a eukaryotic dUTPase, human dUTPase, and complexes with the uracil-containing deoxyribonucleotides, dUMP, dUDP and dUTP. RESULTS. The crystal structure reveals that each subunit of the dUTPase trimer folds into an eight-stranded jelly-roll beta barrel, with the C-terminal beta strands interchanged among the subunits. The structure is similar to that of the E. coli enzyme, despite low sequence homology between the two enzymes. The nucleotide complexes reveal a simple and elegant way for a beta hairpin to recognize specific nucleic acids: uracil is inserted into a distorted antiparallel beta hairpin and hydrogen bonds entirely to main-chain atoms. This interaction mimics DNA base pairing, selecting uracil over cytosine and sterically precluding thymine and ribose binding. Residues from the second subunit interact with the phosphate groups and a glycine-rich C-terminal tail of the third subunit caps the substrate-bound active site, causing total complementary enclosure of substrate. To our knowledge, this is the first documented instance of all three subunits of a trimeric enzyme supplying residues that are critical to enzyme function and catalysis. CONCLUSIONS. The dUTPase nucleotide-binding sites incorporate some features of other nucleotide-binding proteins and protein kinases, but seem distinct in sequence and architecture. The novel nucleic acid base recognition motif appears ancient; higher order structures, such as the ribosome, may have evolved from a motif of this kind. These uracil-beta-hairpin interactions are an obvious way for peptides to become early coenzymes in an RNA world, providing a plausible link to the protein-DNA world. Within the beta hairpin, there is a tyrosine corner motif that normally specifies beta-arch connections; this tyrosine motif was apparently recruited to discriminate against ribonucleotides, more recently than the evolution of the beta hairpin itself.
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*[[DUTPase 3D structures|DUTPase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2HQU is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HQU OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Human dUTP pyrophosphatase: uracil recognition by a beta hairpin and active sites formed by three separate subunits., Mol CD, Harris JM, McIntosh EM, Tainer JA, Structure. 1996 Sep 15;4(9):1077-92. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8805593 8805593]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: dUTP diphosphatase]]
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[[Category: Barabas O]]
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[[Category: Barabas, O.]]
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[[Category: Varga B]]
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[[Category: Varga, B.]]
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[[Category: Vertessy BG]]
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[[Category: Vertessy, B G.]]
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[[Category: CL]]
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[[Category: DUP]]
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[[Category: MG]]
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[[Category: jelly-roll]]
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[[Category: protein-substrate analogue ligand complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 15:16:48 2008''
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Current revision

Human dUTPase in complex with alpha,beta-iminodUTP and magnesium ion

PDB ID 2hqu

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