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| | ==Human purine nucleoside phosphorylase double mutant E201Q,N243D complexed with 2-fluoro-2'-deoxyadenosine== | | ==Human purine nucleoside phosphorylase double mutant E201Q,N243D complexed with 2-fluoro-2'-deoxyadenosine== |
| - | <StructureSection load='3ggs' size='340' side='right' caption='[[3ggs]], [[Resolution|resolution]] 2.52Å' scene=''> | + | <StructureSection load='3ggs' size='340' side='right'caption='[[3ggs]], [[Resolution|resolution]] 2.52Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ggs]] is a 3 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=3GGS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GGS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ggs]] is a 3 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=3GGS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GGS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2FD:5-(6-AMINO-2-FLUORO-PURIN-9-YL)-2-HYDROXYMETHYL-TETRAHYDRO-FURAN-3-OL'>2FD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.52Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3gb9|3gb9]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2FD:5-(6-AMINO-2-FLUORO-PURIN-9-YL)-2-HYDROXYMETHYL-TETRAHYDRO-FURAN-3-OL'>2FD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NP, PNP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3ggs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ggs OCA], [https://pdbe.org/3ggs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ggs RCSB], [https://www.ebi.ac.uk/pdbsum/3ggs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ggs ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] </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=3ggs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ggs OCA], [http://pdbe.org/3ggs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ggs RCSB], [http://www.ebi.ac.uk/pdbsum/3ggs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ggs ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PNPH_HUMAN PNPH_HUMAN]] Defects in PNP are the cause of purine nucleoside phosphorylase deficiency (PNPD) [MIM:[http://omim.org/entry/613179 613179]]. It leads to a severe T-cell immunodeficiency with neurologic disorder in children.<ref>PMID:3029074</ref> <ref>PMID:1384322</ref> <ref>PMID:8931706</ref> | + | [https://www.uniprot.org/uniprot/PNPH_HUMAN PNPH_HUMAN] Defects in PNP are the cause of purine nucleoside phosphorylase deficiency (PNPD) [MIM:[https://omim.org/entry/613179 613179]. It leads to a severe T-cell immunodeficiency with neurologic disorder in children.<ref>PMID:3029074</ref> <ref>PMID:1384322</ref> <ref>PMID:8931706</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PNPH_HUMAN PNPH_HUMAN]] The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.<ref>PMID:2104852</ref> | + | [https://www.uniprot.org/uniprot/PNPH_HUMAN PNPH_HUMAN] The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.<ref>PMID:2104852</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gg/3ggs_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gg/3ggs_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | ==See Also== | | ==See Also== |
| - | *[[Purine nucleoside phosphorylase|Purine nucleoside phosphorylase]] | + | *[[Purine nucleoside phosphorylase 3D structures|Purine nucleoside phosphorylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Purine-nucleoside phosphorylase]] | + | [[Category: Large Structures]] |
| - | [[Category: Afshar, S]] | + | [[Category: Afshar S]] |
| - | [[Category: Sawaya, M R]] | + | [[Category: Sawaya MR]] |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Enzyme-prodrug complex]]
| + | |
| - | [[Category: Glycosyltransferase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
PNPH_HUMAN Defects in PNP are the cause of purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179. It leads to a severe T-cell immunodeficiency with neurologic disorder in children.[1] [2] [3]
Function
PNPH_HUMAN The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.[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
A double mutant of human purine nucleoside phosphorylase (hDM) with the amino acid mutations Glu201Gln:Asn243Asp cleaves adenosine-based prodrugs to their corresponding cytotoxic drugs. When fused to an anti-tumor targeting component, hDM is targeted to tumor cells, where it effectively catalyzes phosphorolysis of the prodrug, 2-fluoro-2'-deoxyadenosine (F-dAdo) to the cytotoxic drug, 2-fluoroadenine (F-Ade). This cytotoxicity should be restricted only to the tumor microenvironment, because the endogenously expressed wild type enzyme cannot use adenosine-based prodrugs as substrates. To gain insight into the interaction of hDM with F-dAdo, we have determined the crystal structures of hDM with F-dAdo and F-Ade. The structures reveal that despite the two mutations, the overall fold of hDM is nearly identical to the wild type enzyme. Importantly, the residues Gln201 and Asp243 introduced by the mutation form hydrogen bond contacts with F-dAdo that result in its binding and catalysis. Comparison of substrate and product complexes suggest that the side chains of Gln201 and Asp243 as well as the purine base rotate during catalysis possibly facilitating cleavage of the glycosidic bond. The two structures suggest why hDM, unlike the wild-type enzyme, can utilize F-dAdo as substrate. More importantly, they provide a critical foundation for further optimization of cleavage of adenosine-based prodrugs, such as F-dAdo by mutants of human purine nucleoside phosphorylase.
Structure of a mutant human purine nucleoside phosphorylase with the prodrug, 2-fluoro-2'-deoxyadenosine and the cytotoxic drug, 2-fluoroadenine.,Afshar S, Sawaya MR, Morrison SL Protein Sci. 2009 May;18(5):1107-14. PMID:19388075[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Williams SR, Gekeler V, McIvor RS, Martin DW Jr. A human purine nucleoside phosphorylase deficiency caused by a single base change. J Biol Chem. 1987 Feb 15;262(5):2332-8. PMID:3029074
- ↑ Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML. Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. Am J Hum Genet. 1992 Oct;51(4):763-72. PMID:1384322
- ↑ Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K. Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. Hum Genet. 1996 Dec;98(6):706-9. PMID:8931706
- ↑ Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR, Stoeckler JD, Parks RE Jr, et al.. Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution. J Biol Chem. 1990 Jan 25;265(3):1812-20. PMID:2104852
- ↑ Afshar S, Sawaya MR, Morrison SL. Structure of a mutant human purine nucleoside phosphorylase with the prodrug, 2-fluoro-2'-deoxyadenosine and the cytotoxic drug, 2-fluoroadenine. Protein Sci. 2009 May;18(5):1107-14. PMID:19388075 doi:10.1002/pro.91
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