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2wwg

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Plasmodium falciparum thymidylate kinase in complex with dGMP and ADP

Structural highlights

2wwg is a 3 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4]

Evolutionary Conservation

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

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kandeel M, Kitade Y. Molecular characterization, heterologous expression and kinetic analysis of recombinant Plasmodium falciparum thymidylate kinase. J Biochem. 2008 Aug;144(2):245-50. PMID:18477629 doi:10.1093/jb/mvn062
↑ Kandeel M, Ando T, Kitamura Y, Abdel-Aziz M, Kitade Y. Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery. Parasitology. 2009 Jan;136(1):11-25. PMID:19126267 doi:10.1017/S0031182008005301
↑ Whittingham JL, Carrero-Lerida J, Brannigan JA, Ruiz-Perez LM, Silva AP, Fogg MJ, Wilkinson AJ, Gilbert IH, Wilson KS, Gonzalez-Pacanowska D. Structural basis for the efficient phosphorylation of AZT-MP (3'-azido-3'-deoxythymidine monophosphate) and dGMP by Plasmodium falciparum type I thymidylate kinase. Biochem J. 2010 May 27;428(3):499-509. PMID:20353400 doi:10.1042/BJ20091880
↑ Chen MD, Fucci IJ, Sinha K, Rule GS. dGMP Binding to Thymidylate Kinase from Plasmodium falciparum Shows Half-Site Binding and Induces Protein Dynamics at the Dimer Interface. Biochemistry. 2020 Feb 11;59(5):694-703. PMID:31934749 doi:10.1021/acs.biochem.9b00898
↑ Whittingham JL, Carrero-Lerida J, Brannigan JA, Ruiz-Perez LM, Silva AP, Fogg MJ, Wilkinson AJ, Gilbert IH, Wilson KS, Gonzalez-Pacanowska D. Structural basis for the efficient phosphorylation of AZT-MP (3'-azido-3'-deoxythymidine monophosphate) and dGMP by Plasmodium falciparum type I thymidylate kinase. Biochem J. 2010 May 27;428(3):499-509. PMID:20353400 doi:10.1042/BJ20091880

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2wwg"

@@ Line 1: / Line 1: @@
 ==Plasmodium falciparum thymidylate kinase in complex with dGMP and ADP==
-<StructureSection load='2wwg' size='340' side='right' caption='[[2wwg]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='2wwg' size='340' side='right'caption='[[2wwg]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2wwg]] is a 3 chain structure with sequence from [http://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=2WWG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WWG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2wwg]] 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=2WWG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WWG 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=DGP:2-DEOXYGUANOSINE-5-MONOPHOSPHATE'>DGP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wwh|2wwh]], [[2wwf|2wwf]], [[2wwi|2wwi]]</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=DGP:2-DEOXYGUANOSINE-5-MONOPHOSPHATE'>DGP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=2wwg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wwg OCA], [https://pdbe.org/2wwg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wwg RCSB], [https://www.ebi.ac.uk/pdbsum/2wwg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wwg ProSAT]</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=2wwg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wwg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wwg RCSB], [http://www.ebi.ac.uk/pdbsum/2wwg PDBsum]</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/2wwg_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ww/2wwg_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].
+</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=2wwg ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 26: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2wwg" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Plasmodium falciparum 3d7]]
+[[Category: Large Structures]]
-[[Category: DTMP kinase]]
+[[Category: Plasmodium falciparum 3D7]]
-[[Category: Brannigan, J A]]
+[[Category: Brannigan JA]]
-[[Category: Carrero-Lerida, J]]
+[[Category: Carrero-Lerida J]]
-[[Category: Fogg, M J]]
+[[Category: Fogg MJ]]
-[[Category: Gilbert, I H]]
+[[Category: Gilbert IH]]
-[[Category: Gonzalez-Pacanowska, D]]
+[[Category: Gonzalez-Pacanowska D]]
-[[Category: Ruiz-Perez, L M]]
+[[Category: Ruiz-Perez LM]]
-[[Category: Silva, A P]]
+[[Category: Silva AP]]
-[[Category: Whittingham, J L]]
+[[Category: Whittingham JL]]
-[[Category: Wilkinson, A J]]
+[[Category: Wilkinson AJ]]
-[[Category: Wilson, K S]]
+[[Category: Wilson KS]]
-[[Category: Kinase]]
-[[Category: Malaria]]
-[[Category: Transferase]]

2wwg

From Proteopedia

Current revision

Plasmodium falciparum thymidylate kinase in complex with dGMP and ADP

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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