1nn1: Difference between revisions

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New page: left|200px<br /> <applet load="1nn1" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nn1, resolution 1.9Å" /> '''Crystal structure of...
 
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[[Image:1nn1.gif|left|200px]]<br />
<applet load="1nn1" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1nn1, resolution 1.9&Aring;" />
'''Crystal structure of human thymidylate kinase with ddTMP and AppNHp'''<br />


==Overview==
==Crystal structure of human thymidylate kinase with ddTMP and AppNHp==
Nucleoside analogue prodrugs are dependent on efficient intracellular, stepwise phosphorylation to their triphosphate form to become, therapeutically active. In many cases it is this activation pathway that, largely determines the efficacy of the drug. To gain further understanding, of the determinants for efficient conversion by the enzyme thymidylate, kinase (TMPK) of clinically important thymidine monophosphate analogues to, the corresponding diphosphates, we solved the crystal structures of the, enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor, site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with, steady-state kinetic data, our structures shed light on the effect of, 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on the, catalytic rate. We observe a direct correlation between the rate of, phosphorylation of an NMP and its ability to induce a closing of the, enzyme's phosphate-binding loop (P-loop). Our results show the drastic, effects that slight modifications of the substrates exert on the enzyme's, conformation and, hence, activity and suggest the type of substitutions, that are compatible with efficient phosphorylation by TMPK.
<StructureSection load='1nn1' size='340' side='right'caption='[[1nn1]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1nn1]] 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=1NN1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NN1 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=2DT:3-DEOXYTHYMIDINE-5-MONOPHOSPHATE'>2DT</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</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=1nn1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nn1 OCA], [https://pdbe.org/1nn1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nn1 RCSB], [https://www.ebi.ac.uk/pdbsum/1nn1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nn1 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/nn/1nn1_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=1nn1 ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
1NN1 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, 2DT and ANP 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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NN1 OCA].
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]]
 
__TOC__
==Reference==
</StructureSection>
Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds., Ostermann N, Segura-Pena D, Meier C, Veit T, Monnerjahn C, Konrad M, Lavie A, Biochemistry. 2003 Mar 11;42(9):2568-77. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12614151 12614151]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: dTMP kinase]]
[[Category: Konrad M]]
[[Category: Konrad, M.]]
[[Category: Lavie A]]
[[Category: Lavie, A.]]
[[Category: Meier C]]
[[Category: Meier, C.]]
[[Category: Monnerjahn M]]
[[Category: Monnerjahn, M.]]
[[Category: Ostermann N]]
[[Category: Ostermann, N.]]
[[Category: Segura-Pena D]]
[[Category: Segura-Pena, D.]]
[[Category: Veit T]]
[[Category: Veit, T.]]
[[Category: 2DT]]
[[Category: ANP]]
[[Category: MG]]
[[Category: dideoxythymidine]]
[[Category: p-loop]]
[[Category: thymidylate kinase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:23:14 2007''

Latest revision as of 10:57, 14 February 2024

Crystal structure of human thymidylate kinase with ddTMP and AppNHpCrystal structure of human thymidylate kinase with ddTMP and AppNHp

Structural highlights

1nn1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KTHY_HUMAN Catalyzes the conversion of dTMP to dTDP.

Evolutionary Conservation

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

See Also

1nn1, resolution 1.90Å

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