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| | <StructureSection load='1uou' size='340' side='right'caption='[[1uou]], [[Resolution|resolution]] 2.11Å' scene=''> | | <StructureSection load='1uou' size='340' side='right'caption='[[1uou]], [[Resolution|resolution]] 2.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1uou]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UOU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1UOU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1uou]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UOU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1UOU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CMU:5-CHLORO-6-(1-(2-IMINOPYRROLIDINYL)+METHYL)+URACIL'>CMU</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]] 2.11Å</td></tr> |
| - | <tr id='activity'><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> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CMU:5-CHLORO-6-(1-(2-IMINOPYRROLIDINYL)+METHYL)+URACIL'>CMU</scene></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=1uou FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uou OCA], [http://pdbe.org/1uou PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1uou RCSB], [http://www.ebi.ac.uk/pdbsum/1uou PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1uou ProSAT]</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=1uou FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uou OCA], [https://pdbe.org/1uou PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1uou RCSB], [https://www.ebi.ac.uk/pdbsum/1uou PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1uou ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://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> |
| | + | == Function == |
| | + | [https://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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Thymidine phosphorylase]]
| + | [[Category: Barry ST]] |
| - | [[Category: Barry, S T]] | + | [[Category: Bate M]] |
| - | [[Category: Bate, M]] | + | [[Category: Breed J]] |
| - | [[Category: Breed, J]] | + | [[Category: Colls JG]] |
| - | [[Category: Colls, J G]] | + | [[Category: Ernill RJ]] |
| - | [[Category: Ernill, R J]] | + | [[Category: Luke RWA]] |
| - | [[Category: Luke, R W.A]] | + | [[Category: McAlister MSB]] |
| - | [[Category: McAlister, M S.B]] | + | [[Category: McCall EJ]] |
| - | [[Category: McCall, E J]] | + | [[Category: McMiken HHJ]] |
| - | [[Category: McMiken, H H.J]] | + | [[Category: Minshull CA]] |
| - | [[Category: Minshull, C A]] | + | [[Category: Norman RA]] |
| - | [[Category: Norman, R A]] | + | [[Category: Paterson DS]] |
| - | [[Category: Paterson, D S]] | + | [[Category: Pauptit RA]] |
| - | [[Category: Pauptit, R A]] | + | [[Category: Timms D]] |
| - | [[Category: Timms, D]] | + | [[Category: Tucker JA]] |
| - | [[Category: Tucker, J A]] | + | |
| - | [[Category: Angiogenesis]]
| + | |
| - | [[Category: Chemotaxis]]
| + | |
| - | [[Category: Glycosyltransferase]]
| + | |
| - | [[Category: Phosphorylase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
TYPH_HUMAN Mitochondrial neurogastrointestinal encephalomyopathy. The disease is caused by mutations affecting the gene represented in this entry.[1] [2]
Function
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.[3] 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.[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
Human thymidine phosphorylase (HTP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is overexpressed in certain solid tumors where it is linked to poor prognosis. HTP expression is utilized for certain chemotherapeutic strategies and is also thought to play a role in tumor angiogenesis. We determined the structure of HTP bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI). The inhibitor appears to mimic the substrate transition state, which may help explain the potency of this inhibitor and the catalytic mechanism of pyrimidine nucleotide phosphorylases (PYNPs). Further, we have confirmed the validity of the HTP structure as a template for structure-based drug design by predicting binding affinities for TPI and other known HTP inhibitors using in silico docking techniques. This work provides the first structural insight into the binding mode of any inhibitor to this important drug target and forms the basis for designing novel inhibitors for use in anticancer therapy.
Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor.,Norman RA, Barry ST, Bate M, Breed J, Colls JG, Ernill RJ, Luke RW, Minshull CA, McAlister MS, McCall EJ, McMiken HH, Paterson DS, Timms D, Tucker JA, Pauptit RA Structure. 2004 Jan;12(1):75-84. PMID:14725767[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999 Jan 29;283(5402):689-92. PMID:9924029
- ↑ Gamez J, Ferreiro C, Accarino ML, Guarner L, Tadesse S, Marti RA, Andreu AL, Raguer N, Cervera C, Hirano M. Phenotypic variability in a Spanish family with MNGIE. Neurology. 2002 Aug 13;59(3):455-7. PMID:12177387
- ↑ Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun. 1992 May 15;184(3):1311-6. PMID:1590793
- ↑ Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH. Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun. 1992 May 15;184(3):1311-6. PMID:1590793
- ↑ Norman RA, Barry ST, Bate M, Breed J, Colls JG, Ernill RJ, Luke RW, Minshull CA, McAlister MS, McCall EJ, McMiken HH, Paterson DS, Timms D, Tucker JA, Pauptit RA. Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Structure. 2004 Jan;12(1):75-84. PMID:14725767
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