1e9c

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[[Image:1e9c.jpg|left|200px]]<br /><applet load="1e9c" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1e9c, resolution 1.6&Aring;" />
 
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'''MUTANT HUMAN THYMIDYLATE KINASE COMPLEXED WITH TMP AND APPNP'''<br />
 
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==Overview==
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==Mutant human thymidylate kinase complexed with TMP and APPNP==
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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.
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<StructureSection load='1e9c' size='340' side='right'caption='[[1e9c]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1e9c]] 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=1E9C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1E9C 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]] 1.6&#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=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TMP:THYMIDINE-5-PHOSPHATE'>TMP</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=1e9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e9c OCA], [https://pdbe.org/1e9c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1e9c RCSB], [https://www.ebi.ac.uk/pdbsum/1e9c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1e9c ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/KTHY_HUMAN KTHY_HUMAN] Catalyzes the conversion of dTMP to dTDP.
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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/e9/1e9c_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=1e9c 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 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.
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==About this Structure==
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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>
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1E9C 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, TMP and ADP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] Known structural/functional Site: <scene name='pdbsite=TMP:Anp Binding Site'>TMP</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1E9C 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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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]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1e9c" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: dTMP kinase]]
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[[Category: Brundiers, R.]]
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[[Category: Goody, R.S.]]
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[[Category: Konrad, M.]]
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[[Category: Lavie, A.]]
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[[Category: Ostermann, N.]]
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[[Category: Padiyar, S.]]
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[[Category: Reinstein, J.]]
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[[Category: Schlichting, I.]]
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[[Category: Veit, T.]]
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[[Category: ADP]]
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[[Category: MG]]
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[[Category: TMP]]
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[[Category: p-loop]]
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[[Category: thymidylate kinase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 15:05:18 2007''
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==See Also==
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*[[Thymidylate kinase 3D structures|Thymidylate kinase 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: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Brundiers R]]
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[[Category: Goody RS]]
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[[Category: Konrad M]]
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[[Category: Lavie A]]
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[[Category: Ostermann N]]
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[[Category: Padiyar S]]
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[[Category: Reintein J]]
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[[Category: Schlichting I]]
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[[Category: Veit T]]

Current revision

Mutant human thymidylate kinase complexed with TMP and APPNP

PDB ID 1e9c

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