2j0f

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[[Image:2j0f.png|left|200px]]
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==STRUCTURAL BASIS FOR NON-COMPETITIVE PRODUCT INHIBITION IN HUMAN THYMIDINE PHOSPHORYLASE: IMPLICATION FOR DRUG DESIGN==
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<StructureSection load='2j0f' size='340' side='right' caption='[[2j0f]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2j0f]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J0F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2J0F FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TDR:THYMINE'>TDR</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1uou|1uou]]</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thymidine_phosphorylase Thymidine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.4 2.4.2.4] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2j0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j0f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2j0f RCSB], [http://www.ebi.ac.uk/pdbsum/2j0f PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/TYPH_HUMAN TYPH_HUMAN]] Mitochondrial neurogastrointestinal encephalomyopathy. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:9924029</ref> <ref>PMID:12177387</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/TYPH_HUMAN TYPH_HUMAN]] May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro.<ref>PMID:1590793</ref> Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.<ref>PMID:1590793</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j0/2j0f_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
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{{STRUCTURE_2j0f| PDB=2j0f | SCENE= }}
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Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design.,El Omari K, Bronckaers A, Liekens S, Perez-Perez MJ, Balzarini J, Stammers DK Biochem J. 2006 Oct 15;399(2):199-204. PMID:16803458<ref>PMID:16803458</ref>
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===STRUCTURAL BASIS FOR NON-COMPETITIVE PRODUCT INHIBITION IN HUMAN THYMIDINE PHOSPHORYLASE: IMPLICATION FOR DRUG DESIGN===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_16803458}}
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== References ==
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<references/>
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==About this Structure==
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__TOC__
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[[2j0f]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J0F OCA].
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:016803458</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Thymidine phosphorylase]]
[[Category: Thymidine phosphorylase]]

Revision as of 08:09, 30 September 2014

STRUCTURAL BASIS FOR NON-COMPETITIVE PRODUCT INHIBITION IN HUMAN THYMIDINE PHOSPHORYLASE: IMPLICATION FOR DRUG DESIGN

2j0f, resolution 2.31Å

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