2w0s: Difference between revisions
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< | ==Crystal structure of vaccinia virus thymidylate kinase bound to brivudin-5'-monophosphate== | ||
<StructureSection load='2w0s' size='340' side='right'caption='[[2w0s]], [[Resolution|resolution]] 2.92Å' scene=''> | |||
You may | == Structural highlights == | ||
or the | <table><tr><td colspan='2'>[[2w0s]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Vaccinia_virus_Copenhagen Vaccinia virus Copenhagen]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W0S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W0S 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]] 2.918Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BVP:(E)-5-(2-BROMOVINYL)-2-DEOXYURIDINE-5-MONOPHOSPHATE'>BVP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2w0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w0s OCA], [https://pdbe.org/2w0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w0s RCSB], [https://www.ebi.ac.uk/pdbsum/2w0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w0s ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KTHY_VACCC KTHY_VACCC] Poxvirus TMP kinase is able to phosphorylate dTMP, dUMP and also dGMP from any purine and pyrimidine nucleoside triphosphate. The large substrate specificity is explained by the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket, canal not found in the human homolog (By similarity). | |||
== 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/w0/2w0s_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=2w0s ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer. | |||
Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy.,Caillat C, Topalis D, Agrofoglio LA, Pochet S, Balzarini J, Deville-Bonne D, Meyer P Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16900-5. Epub 2008 Oct 29. PMID:18971333<ref>PMID:18971333</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2w0s" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] | |||
[[Category: | == References == | ||
[[Category: Vaccinia virus | <references/> | ||
__TOC__ | |||
[[Category: Agrofoglio | </StructureSection> | ||
[[Category: Balzarini | [[Category: Large Structures]] | ||
[[Category: Caillat | [[Category: Vaccinia virus Copenhagen]] | ||
[[Category: Deville-Bonne | [[Category: Agrofoglio LA]] | ||
[[Category: Meyer | [[Category: Balzarini J]] | ||
[[Category: Pochet | [[Category: Caillat C]] | ||
[[Category: Topalis | [[Category: Deville-Bonne D]] | ||
[[Category: Meyer P]] | |||
[[Category: Pochet S]] | |||
[[Category: Topalis D]] | |||
Latest revision as of 18:39, 13 December 2023
Crystal structure of vaccinia virus thymidylate kinase bound to brivudin-5'-monophosphateCrystal structure of vaccinia virus thymidylate kinase bound to brivudin-5'-monophosphate
Structural highlights
FunctionKTHY_VACCC Poxvirus TMP kinase is able to phosphorylate dTMP, dUMP and also dGMP from any purine and pyrimidine nucleoside triphosphate. The large substrate specificity is explained by the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket, canal not found in the human homolog (By similarity). 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 PubMedUnlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer. Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy.,Caillat C, Topalis D, Agrofoglio LA, Pochet S, Balzarini J, Deville-Bonne D, Meyer P Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16900-5. Epub 2008 Oct 29. PMID:18971333[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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