2wwf: Difference between revisions
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==PLASMODIUM FALCIPARUM THYMIDYLATE KINASE IN COMPLEX WITH TMP AND ADP== | |||
<StructureSection load='2wwf' size='340' side='right' caption='[[2wwf]], [[Resolution|resolution]] 1.89Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2wwf]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WWF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WWF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TMP:THYMIDINE-5-PHOSPHATE'>TMP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wwh|2wwh]], [[2wwg|2wwg]], [[2wwi|2wwi]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wwf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wwf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wwf RCSB], [http://www.ebi.ac.uk/pdbsum/2wwf PDBsum]</span></td></tr> | |||
</table> | |||
== 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/ww/2wwf_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/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Plasmodium falciparum is the causative agent of malaria, a disease where new drug targets are required due to increasing resistance to current anti-malarials. TMPK (thymidylate kinase) is a good candidate as it is essential for the synthesis of dTTP, a critical precursor of DNA and has been much studied due to its role in prodrug activation and as a drug target. Type I TMPKs, such as the human enzyme, phosphorylate the substrate AZT (3'-azido-3'-deoxythymidine)-MP (monophosphate) inefficiently compared with type II TMPKs (e.g. Escherichia coli TMPK). In the present paper we report that eukaryotic PfTMPK (P. falciparum TMPK) presents sequence features of a type I enzyme yet the kinetic parameters for AZT-MP phosphorylation are similar to those of the highly efficient E. coli enzyme. Structural information shows that this is explained by a different juxtaposition of the P-loop and the azide of AZT-MP. Subsequent formation of the transition state requires no further movement of the PfTMPK P-loop, with no steric conflicts for the azide moiety, allowing efficient phosphate transfer. Likewise, we present results that confirm the ability of the enzyme to uniquely accept dGMP as a substrate and shed light on the basis for its wider substrate specificity. Information resulting from two ternary complexes (dTMP-ADP and AZT-MP-ADP) and a binary complex with the transition state analogue AP5dT [P1-(5'-adenosyl)-P5-(5'-thymidyl) pentaphosphate] all reveal significant differences with the human enzyme, notably in the lid region and in the P-loop which may be exploited in the rational design of Plasmodium-specific TMPK inhibitors with therapeutic potential. | |||
Structural basis for the efficient phosphorylation of AZT-MP (3'-azido-3'-deoxythymidine monophosphate) and dGMP by Plasmodium falciparum type I thymidylate kinase.,Whittingham JL, Carrero-Lerida J, Brannigan JA, Ruiz-Perez LM, Silva AP, Fogg MJ, Wilkinson AJ, Gilbert IH, Wilson KS, Gonzalez-Pacanowska D Biochem J. 2010 May 27;428(3):499-509. PMID:20353400<ref>PMID:20353400</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Plasmodium falciparum]] | [[Category: Plasmodium falciparum]] | ||
[[Category: DTMP kinase]] | [[Category: DTMP kinase]] | ||
[[Category: Brannigan, J A | [[Category: Brannigan, J A]] | ||
[[Category: Carrero-Lerida, J | [[Category: Carrero-Lerida, J]] | ||
[[Category: Fogg, M J | [[Category: Fogg, M J]] | ||
[[Category: Gilbert, I H | [[Category: Gilbert, I H]] | ||
[[Category: Gonzalez-Pacanowska, D | [[Category: Gonzalez-Pacanowska, D]] | ||
[[Category: Perez, L M.Ruiz- | [[Category: Perez, L M.Ruiz-]] | ||
[[Category: Silva, A P.G | [[Category: Silva, A P.G]] | ||
[[Category: Whittingham, J L | [[Category: Whittingham, J L]] | ||
[[Category: Wilkinson, A J | [[Category: Wilkinson, A J]] | ||
[[Category: Wilson, K S | [[Category: Wilson, K S]] | ||
[[Category: Kinase]] | [[Category: Kinase]] | ||
[[Category: Malaria]] | [[Category: Malaria]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||