2wwh: Difference between revisions

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-[[Image:2wwh.png|left|200px]]
-<!--
+==Plasmodium falciparum thymidylate kinase in complex with AP5dT==
-The line below this paragraph, containing "STRUCTURE_2wwh", creates the "Structure Box" on the page.
+<StructureSection load='2wwh' size='340' side='right'caption='[[2wwh]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2wwh]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WWH FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=T5A:P1-(5-ADENOSYL)P5-(5-THYMIDYL)PENTAPHOSPHATE'>T5A</scene></td></tr>
-{{STRUCTURE_2wwh|  PDB=2wwh  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2wwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wwh OCA], [https://pdbe.org/2wwh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wwh RCSB], [https://www.ebi.ac.uk/pdbsum/2wwh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wwh ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/KTHY_PLAF7 KTHY_PLAF7] Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can also phosphorylate dGMP and to a lesser extent GMP, dUMP and dIMP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can use either ATP or dATP as phosphate donors in presence of Mg(2+) (PubMed:18477629).<ref>PMID:18477629</ref> <ref>PMID:19126267</ref> <ref>PMID:20353400</ref> <ref>PMID:31934749</ref>
+== 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/2wwh_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=2wwh 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.
-===PLASMODIUM FALCIPARUM THYMIDYLATE KINASE IN COMPLEX WITH AP5DT===
+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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<!--
+</div>
-The line below this paragraph, {{ABSTRACT_PUBMED_20353400}}, adds the Publication Abstract to the page
+<div class="pdbe-citations 2wwh" style="background-color:#fffaf0;"></div>
-(as it appears on PubMed at http://www.pubmed.gov), where 20353400 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_20353400}}
+__TOC__
+</StructureSection>
-==About this Structure==
+[[Category: Large Structures]]
-[[2wwh]] 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=2WWH OCA].
+[[Category: Plasmodium falciparum 3D7]]
+[[Category: Brannigan JA]]
-==Reference==
+[[Category: Carrero-Lerida J]]
-<ref group="xtra">PMID:20353400</ref><references group="xtra"/>
+[[Category: Fogg MJ]]
-[[Category: Plasmodium falciparum]]
+[[Category: Gilbert IH]]
-[[Category: DTMP kinase]]
+[[Category: Gonzalez-Pacanowska D]]
-[[Category: Brannigan, J A.]]
+[[Category: Ruiz-Perez LM]]
-[[Category: Carrero-Lerida, J.]]
+[[Category: Silva APG]]
-[[Category: Fogg, M J.]]
+[[Category: Whittingham JL]]
-[[Category: Gilbert, I H.]]
+[[Category: Wilkinson AJ]]
-[[Category: Gonzalez-Pacanowska, D.]]
+[[Category: Wilson KS]]
-[[Category: Perez, L M.Ruiz-.]]
-[[Category: Silva, A P.G.]]
-[[Category: Whittingham, J L.]]
-[[Category: Wilkinson, A J.]]
-[[Category: Wilson, K S.]]
-[[Category: Malaria]]
-[[Category: Transferase]]