1sm8

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(New page: 200px<br /><applet load="1sm8" size="450" color="white" frame="true" align="right" spinBox="true" caption="1sm8, resolution 2.90&Aring;" /> '''M. tuberculosis dUTP...)
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[[Image:1sm8.gif|left|200px]]<br /><applet load="1sm8" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1sm8, resolution 2.90&Aring;" />
 
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'''M. tuberculosis dUTPase complexed with chromium and dUTP'''<br />
 
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==Overview==
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==M. tuberculosis dUTPase complexed with chromium and dUTP==
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The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase, (dUTPase) has been determined at 1.3 Angstrom resolution in complex with, magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido, dUTP. dUTPase is an enzyme essential for depleting potentially toxic, concentrations of dUTP in the cell. Given the importance of its biological, role, it has been proposed that inhibiting M.tuberculosis dUTPase might be, an effective means to treat tuberculosis infection in humans. The crystal, structure presented here offers some insight into the potential for, designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The, structure also offers new insights into the mechanism of dUTP hydrolysis, by providing an accurate representation of the enzyme-substrate complex in, which both the metal ion and dUTP analog are included. The structure, suggests that inclusion of a magnesium ion is important for stabilizing, the position of the alpha-phosphorus for an in-line nucleophilic attack., In the absence of magnesium, the alpha-phosphate of dUTP can have either, of the two positions which differ by 4.5 Angstrom. A transiently ordered, C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn, activate a tightly bound water molecule for nucleophilic attack. The metal, ion coordinates alpha, beta, and gamma phosphate groups with tridentate, geometry identical with that observed in the crystal structure of DNA, polymerase beta complexed with magnesium and dNTP analog, revealing some, common features in catalytic mechanism.
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<StructureSection load='1sm8' size='340' side='right'caption='[[1sm8]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1sm8]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SM8 FirstGlance]. <br>
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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]] 2.9&#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=CR:CHROMIUM+ION'>CR</scene>, <scene name='pdbligand=DUT:DEOXYURIDINE-5-TRIPHOSPHATE'>DUT</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
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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=1sm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sm8 OCA], [https://pdbe.org/1sm8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1sm8 RCSB], [https://www.ebi.ac.uk/pdbsum/1sm8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1sm8 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DUT_MYCTU DUT_MYCTU] 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.[HAMAP-Rule:MF_00116]
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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/sm/1sm8_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=1sm8 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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The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase (dUTPase) has been determined at 1.3 Angstrom resolution in complex with magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido dUTP. dUTPase is an enzyme essential for depleting potentially toxic concentrations of dUTP in the cell. Given the importance of its biological role, it has been proposed that inhibiting M.tuberculosis dUTPase might be an effective means to treat tuberculosis infection in humans. The crystal structure presented here offers some insight into the potential for designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The structure also offers new insights into the mechanism of dUTP hydrolysis by providing an accurate representation of the enzyme-substrate complex in which both the metal ion and dUTP analog are included. The structure suggests that inclusion of a magnesium ion is important for stabilizing the position of the alpha-phosphorus for an in-line nucleophilic attack. In the absence of magnesium, the alpha-phosphate of dUTP can have either of the two positions which differ by 4.5 Angstrom. A transiently ordered C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn activate a tightly bound water molecule for nucleophilic attack. The metal ion coordinates alpha, beta, and gamma phosphate groups with tridentate geometry identical with that observed in the crystal structure of DNA polymerase beta complexed with magnesium and dNTP analog, revealing some common features in catalytic mechanism.
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==About this Structure==
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Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism.,Chan S, Segelke B, Lekin T, Krupka H, Cho US, Kim MY, So M, Kim CY, Naranjo CM, Rogers YC, Park MS, Waldo GS, Pashkov I, Cascio D, Perry JL, Sawaya MR J Mol Biol. 2004 Aug 6;341(2):503-17. PMID:15276840<ref>PMID:15276840</ref>
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1SM8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with CR, NO3, DUT and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1SM8 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism., Chan S, Segelke B, Lekin T, Krupka H, Cho US, Kim MY, So M, Kim CY, Naranjo CM, Rogers YC, Park MS, Waldo GS, Pashkov I, Cascio D, Perry JL, Sawaya MR, J Mol Biol. 2004 Aug 6;341(2):503-17. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15276840 15276840]
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</div>
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[[Category: Mycobacterium tuberculosis]]
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<div class="pdbe-citations 1sm8" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: dUTP diphosphatase]]
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[[Category: Cascio, D.]]
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[[Category: Chan, S.]]
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[[Category: Cho, U.S.]]
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[[Category: Eisenberg, D.]]
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[[Category: Kim, C.Y.]]
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[[Category: Kim, M.Y.]]
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[[Category: Krupka, H.]]
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[[Category: Lekin, T.]]
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[[Category: Naranjo, C.M.]]
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[[Category: Park, M.S.]]
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[[Category: Pashkov, I.]]
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[[Category: Perry, J.L.]]
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[[Category: Rogers, Y.C.]]
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[[Category: Sawaya, M.R.]]
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[[Category: Segelke, B.]]
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[[Category: So, M.]]
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[[Category: TBSGC, TB.Structural.Genomics.Consortium.]]
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[[Category: Terwilliger, T.C.]]
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[[Category: Waldo, G.S.]]
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[[Category: Yeates, T.O.]]
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[[Category: CR]]
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[[Category: DUT]]
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[[Category: NO3]]
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[[Category: TRS]]
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[[Category: jelly-roll]]
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[[Category: protein structure initiative]]
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[[Category: psi]]
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[[Category: structural genomics]]
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[[Category: tb structural genomics consortium]]
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[[Category: tbsgc]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 02:28:50 2007''
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==See Also==
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*[[DUTPase 3D structures|DUTPase 3D structures]]
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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]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Cascio D]]
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[[Category: Chan S]]
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[[Category: Cho US]]
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[[Category: Eisenberg D]]
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[[Category: Kim C-Y]]
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[[Category: Kim M-Y]]
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[[Category: Krupka H]]
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[[Category: Lekin T]]
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[[Category: Naranjo CM]]
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[[Category: Park MS]]
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[[Category: Pashkov I]]
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[[Category: Perry JL]]
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[[Category: Rogers YC]]
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[[Category: Sawaya MR]]
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[[Category: Segelke B]]
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[[Category: So M]]
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[[Category: Terwilliger TC]]
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[[Category: Waldo GS]]
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[[Category: Yeates TO]]

Current revision

M. tuberculosis dUTPase complexed with chromium and dUTP

PDB ID 1sm8

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