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| | ==Crystal structure of D12N variant of mouse cytosolic 5'(3')- deoxyribonucleotidase (cdN) in complex with deoxyguanosine 5'- monophosphate== | | ==Crystal structure of D12N variant of mouse cytosolic 5'(3')- deoxyribonucleotidase (cdN) in complex with deoxyguanosine 5'- monophosphate== |
| - | <StructureSection load='2jao' size='340' side='right' caption='[[2jao]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='2jao' size='340' side='right'caption='[[2jao]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2jao]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JAO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2JAO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2jao]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JAO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DGP:2-DEOXYGUANOSINE-5-MONOPHOSPHATE'>DGP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jar|2jar]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DGP:2-DEOXYGUANOSINE-5-MONOPHOSPHATE'>DGP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2jao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jao OCA], [http://pdbe.org/2jao PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2jao RCSB], [http://www.ebi.ac.uk/pdbsum/2jao PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2jao 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=2jao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jao OCA], [https://pdbe.org/2jao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jao RCSB], [https://www.ebi.ac.uk/pdbsum/2jao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jao ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NT5C_MOUSE NT5C_MOUSE]] Dephosphorylates the 5' and 2'(3')-phosphates of deoxyribonucleotides, with a preference for dUMP and dTMP, intermediate activity towards dGMP, and low activity towards dCMP and dAMP.<ref>PMID:10681516</ref> | + | [https://www.uniprot.org/uniprot/NT5C_MOUSE NT5C_MOUSE] Dephosphorylates the 5' and 2'(3')-phosphates of deoxyribonucleotides, with a preference for dUMP and dTMP, intermediate activity towards dGMP, and low activity towards dCMP and dAMP.<ref>PMID:10681516</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: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Bianchi, V]] | + | [[Category: Mus musculus]] |
| - | [[Category: Nordlund, P]] | + | [[Category: Bianchi V]] |
| - | [[Category: Ruzzenente, B]] | + | [[Category: Nordlund P]] |
| - | [[Category: Wallden, K]] | + | [[Category: Ruzzenente B]] |
| - | [[Category: Alpha-beta fold]]
| + | [[Category: Wallden K]] |
| - | [[Category: Cytosol]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Magnesium]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nucleotide metabolism]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| Structural highlights
Function
NT5C_MOUSE Dephosphorylates the 5' and 2'(3')-phosphates of deoxyribonucleotides, with a preference for dUMP and dTMP, intermediate activity towards dGMP, and low activity towards dCMP and dAMP.[1]
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
Cytosolic 5'(3')-deoxyribonucleotidase (cdN) and mitochondrial 5'(3')-deoxyribonucleotidase (mdN) catalyze the dephosphorylation of deoxyribonucleoside monophosphates and regulate dTTP formation in cytosol and mitochondria, protecting DNA replication from imbalanced precursor pools. They can also interfere with the phosphorylation-dependent activation of nucleoside analogues used in anticancer and antiviral treatment. To understand the relatively narrow substrate specificity of these two enzymes and their ability to use nucleotide analogues as substrates, we determined the crystal structures of human cdN in complex with deoxyuridine, murine cdN in complex with dUMP and dGMP, and human mdN in complex with the nucleotide analogues AZTMP and BVdUMP. Our results show that the active site residues Leu45 and Tyr65 in cdN form a more favorable binding surface for purine nucleotides than the corresponding Trp75 and Trp76 in mdN, explaining why cdN has higher activity for purine nucleotides than does mdN. The molecular interactions of mdN with AZTMP and BVdUMP indicate why these nucleotide analogues are poorer substrates as compared with the physiological substrate, and they provide a structural rationale for the design of drugs that are less prone to inactivation by the deoxyribonucleotidases. We suggest that introduction of substituents in the 3'-position may result in nucleoside analogues with increased resistance to dephosphorylation.
Crystal structures of human and murine deoxyribonucleotidases: insights into recognition of substrates and nucleotide analogues.,Wallden K, Rinaldo-Matthis A, Ruzzenente B, Rampazzo C, Bianchi V, Nordlund P Biochemistry. 2007 Dec 4;46(48):13809-18. Epub 2007 Nov 7. PMID:17985935[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rampazzo C, Johansson M, Gallinaro L, Ferraro P, Hellman U, Karlsson A, Reichard P, Bianchi V. Mammalian 5'(3')-deoxyribonucleotidase, cDNA cloning, and overexpression of the enzyme in Escherichia coli and mammalian cells. J Biol Chem. 2000 Feb 25;275(8):5409-15. PMID:10681516
- ↑ Wallden K, Rinaldo-Matthis A, Ruzzenente B, Rampazzo C, Bianchi V, Nordlund P. Crystal structures of human and murine deoxyribonucleotidases: insights into recognition of substrates and nucleotide analogues. Biochemistry. 2007 Dec 4;46(48):13809-18. Epub 2007 Nov 7. PMID:17985935 doi:10.1021/bi7014794
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