1e98: Difference between revisions

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New page: left|200px<br /> <applet load="1e98" size="450" color="white" frame="true" align="right" spinBox="true" caption="1e98, resolution 1.9Å" /> '''WILD TYPE HUMAN THYM...
 
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[[Image:1e98.gif|left|200px]]<br />
<applet load="1e98" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1e98, resolution 1.9&Aring;" />
'''WILD TYPE HUMAN THYMIDYLATE KINASE COMPLEXED WITH AZTMP AND ADP'''<br />


==Overview==
==Wild type human thymidylate kinase complexed with AZTMP and ADP==
The 60-fold reduced phosphorylation rate of azidothymidine (AZT), monophosphate (AZTMP), the partially activated AZT metabolite, by human, thymidylate kinase (TMPK) severely limits the efficacy of this anti-HIV, prodrug. Crystal structures of different TMPK nucleotide complexes, indicate that steric hindrance by the azido group of AZTMP prevents, formation of the catalytically active closed conformation of the P-loop of, TMPK. The F105Y mutant and a chimeric mutant that contains sequences of, the human and Escherichia coli enzyme phosphorylate AZTMP 20-fold faster, than the wild-type enzyme. The structural basis of the increased activity, is assigned to stabilization of the closed P-loop conformation.
<StructureSection load='1e98' size='340' side='right'caption='[[1e98]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1e98]] is a 1 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=1E98 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E98 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=ATM:3-AZIDO-3-DEOXYTHYMIDINE-5-MONOPHOSPHATE'>ATM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=1e98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e98 OCA], [https://pdbe.org/1e98 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e98 RCSB], [https://www.ebi.ac.uk/pdbsum/1e98 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e98 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KTHY_HUMAN KTHY_HUMAN] Catalyzes the conversion of dTMP to dTDP.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/e9/1e98_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </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/main_output.php?pdb_ID=1e98 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The 60-fold reduced phosphorylation rate of azidothymidine (AZT) monophosphate (AZTMP), the partially activated AZT metabolite, by human thymidylate kinase (TMPK) severely limits the efficacy of this anti-HIV prodrug. Crystal structures of different TMPK nucleotide complexes indicate that steric hindrance by the azido group of AZTMP prevents formation of the catalytically active closed conformation of the P-loop of TMPK. The F105Y mutant and a chimeric mutant that contains sequences of the human and Escherichia coli enzyme phosphorylate AZTMP 20-fold faster than the wild-type enzyme. The structural basis of the increased activity is assigned to stabilization of the closed P-loop conformation.


==About this Structure==
Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants' improved kinetics with the HIV prodrug metabolite AZTMP.,Ostermann N, Lavie A, Padiyar S, Brundiers R, Veit T, Reinstein J, Goody RS, Konrad M, Schlichting I J Mol Biol. 2000 Nov 17;304(1):43-53. PMID:11071809<ref>PMID:11071809</ref>
1E98 is a [[http://en.wikipedia.org/wiki/Single_protein Single protein]] structure of sequence from [[http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]] with MG, ADP and ATM as [[http://en.wikipedia.org/wiki/ligands ligands]]. Active as [[http://en.wikipedia.org/wiki/ ]], with EC number [[http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9]]. Full crystallographic information is available from [[http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1E98 OCA]].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants' improved kinetics with the HIV prodrug metabolite AZTMP., Ostermann N, Lavie A, Padiyar S, Brundiers R, Veit T, Reinstein J, Goody RS, Konrad M, Schlichting I, J Mol Biol. 2000 Nov 17;304(1):43-53. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11071809 11071809]
</div>
<div class="pdbe-citations 1e98" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Brundiers, R.]]
[[Category: Brundiers R]]
[[Category: Goody, R.S.]]
[[Category: Goody RS]]
[[Category: Konrad, M.]]
[[Category: Konrad M]]
[[Category: Lavie, A.]]
[[Category: Lavie A]]
[[Category: Ostermann, N.]]
[[Category: Ostermann N]]
[[Category: Padiyar, S.]]
[[Category: Padiyar S]]
[[Category: Reintein, J.]]
[[Category: Reintein J]]
[[Category: Schlichting, I.]]
[[Category: Schlichting I]]
[[Category: Veit, T.]]
[[Category: Veit T]]
[[Category: ADP]]
[[Category: ATM]]
[[Category: MG]]
[[Category: p-loop]]
[[Category: thymidylate kinase]]
 
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Retrieved from "https://proteopedia.org/1e98"