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| | <StructureSection load='2a7q' size='340' side='right'caption='[[2a7q]], [[Resolution|resolution]] 2.55Å' scene=''> | | <StructureSection load='2a7q' size='340' side='right'caption='[[2a7q]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2a7q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A7Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A7Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2a7q]] 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=2A7Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A7Q FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CFB:2-CHLORO-9-(2-DEOXY-2-FLUORO-B+-D-ARABINOFURANOSYL)-9H-PURIN-6-AMINE'>CFB</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]] 2.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1p5z|1p5z]], [[1p60|1p60]], [[1p61|1p61]], [[1p62|1p62]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CFB:2-CHLORO-9-(2-DEOXY-2-FLUORO-B+-D-ARABINOFURANOSYL)-9H-PURIN-6-AMINE'>CFB</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DCK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74] </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=2a7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7q OCA], [https://pdbe.org/2a7q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a7q RCSB], [https://www.ebi.ac.uk/pdbsum/2a7q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a7q 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=2a7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7q OCA], [https://pdbe.org/2a7q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a7q RCSB], [https://www.ebi.ac.uk/pdbsum/2a7q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a7q ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/DCK_HUMAN DCK_HUMAN]] Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.<ref>PMID:18377927</ref> <ref>PMID:20614893</ref>
| + | [https://www.uniprot.org/uniprot/DCK_HUMAN DCK_HUMAN] Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.<ref>PMID:18377927</ref> <ref>PMID:20614893</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: Deoxycytidine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ealick, S E]] | + | [[Category: Ealick SE]] |
| - | [[Category: III, J A.Secrist]] | + | [[Category: Secrist III JA]] |
| - | [[Category: Zhang, Y]] | + | [[Category: Zhang Y]] |
| - | [[Category: Alpha/beta parallel beta-sheet of 5 strand]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
DCK_HUMAN Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.[1] [2]
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
Clofarabine [2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine] is a hybrid of the widely used anticancer drugs cladribine and fludarabine. It is the precursor of an effective chemotherapeutic agent for leukemias and other hematological malignancies and received accelerated approval by the FDA for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia. Clofarabine is phosphorylated intracellularly by human deoxycytidine kinase (dCK) to the 5'-monophosphate, which is the rate-limiting step in activation of the prodrug. dCK has a broad substrate specificity, with a much higher activity to deoxycytidine than to deoxyadenosine and deoxyguanosine. As a purine-nucleoside analog, clofarabine is a better substrate of dCK than deoxycytidine. The crystal structure of dCK has been solved previously in complex with pyrimidine nucleosides and ADP [Sabini et al. (2003), Nature Struct. Biol. 10, 513-519]. In the current study, the crystal structure of clofarabine- and ADP-bound dCK was solved to 2.55 angstroms by molecular replacement. It appears that the enzyme takes the same conformation as in the structures of the pyrimidine nucleoside-bound complexes. The interactions between 2-Cl and its surrounding hydrophobic residues contribute to the high catalytic efficiency of dCK for clofarabine.
The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation.,Zhang Y, Secrist JA 3rd, Ealick SE Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006, Jan 18. PMID:16421443[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sabini E, Hazra S, Ort S, Konrad M, Lavie A. Structural basis for substrate promiscuity of dCK. J Mol Biol. 2008 May 2;378(3):607-21. Epub 2008 Mar 3. PMID:18377927 doi:http://dx.doi.org/10.1016/j.jmb.2008.02.061
- ↑ Hazra S, Ort S, Konrad M, Lavie A. Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues . Biochemistry. 2010 Aug 10;49(31):6784-90. PMID:20614893 doi:10.1021/bi100839e
- ↑ Zhang Y, Secrist JA 3rd, Ealick SE. The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation. Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006, Jan 18. PMID:16421443 doi:http://dx.doi.org/10.1107/S0907444905034293
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