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| | ==C4S dCK variant of dCK in complex with cladribine+UDP== | | ==C4S dCK variant of dCK in complex with cladribine+UDP== |
| - | <StructureSection load='2zia' size='340' side='right' caption='[[2zia]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='2zia' size='340' side='right'caption='[[2zia]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2zia]] is a 2 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=2ZIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZIA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2zia]] is a 2 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=2ZIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZIA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL9:2-CHLORO-2-DEOXYADENOSINE'>CL9</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1p60|1p60]], [[2no1|2no1]], [[2no7|2no7]], [[2zi3|2zi3]], [[2zi4|2zi4]], [[2zi5|2zi5]], [[2zi6|2zi6]], [[2zi7|2zi7]], [[2zi9|2zi9]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL9:2-CHLORO-2-DEOXYADENOSINE'>CL9</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DCK ([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=2zia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zia OCA], [https://pdbe.org/2zia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zia RCSB], [https://www.ebi.ac.uk/pdbsum/2zia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zia 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/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74] </span></td></tr>
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| - | <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=2zia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zia OCA], [http://pdbe.org/2zia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zia RCSB], [http://www.ebi.ac.uk/pdbsum/2zia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zia ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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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| | ==See Also== | | ==See Also== |
| - | *[[Deoxycytidine kinase|Deoxycytidine kinase]] | + | *[[ATPase 3D structures|ATPase 3D structures]] |
| | + | *[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Deoxycytidine kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Lavie, A]] | + | [[Category: Lavie A]] |
| - | [[Category: Sabini, E]] | + | [[Category: Sabini E]] |
| - | [[Category: 2-chloro-2'-deoxyadenosine]]
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| - | [[Category: Atp-binding]]
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| - | [[Category: Cladribine]]
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| - | [[Category: Dck]]
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| - | [[Category: Deoxyadenosine analog]]
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| - | [[Category: Nucleoside]]
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| - | [[Category: Nucleotide-binding]]
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| - | [[Category: Nucleus]]
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| - | [[Category: Phosphoprotein]]
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| - | [[Category: Purine]]
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| - | [[Category: Transferase]]
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| - | [[Category: Udp]]
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| 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
Purine nucleoside analogues of medicinal importance, such as cladribine, require phosphorylation by deoxycytidine kinase (dCK) for pharmacological activity. Structural studies of ternary complexes of human dCK show that the enzyme conformation adjusts to the different hydrogen-bonding properties between dA and dG and to the presence of substituent at the 2-position present in dG and cladribine. Specifically, the carbonyl group in dG elicits a previously unseen conformational adjustment of the active site residues Arg104 and Asp133. In addition, dG and cladribine adopt the anti conformation, in contrast to the syn conformation observed with dA. Kinetic analysis reveals that cladribine is phosphorylated at the highest efficiency with UTP as donor. We attribute this to the ability of cladribine to combine advantageous properties from dA (favorable hydrogen-bonding pattern) and dG (propensity to bind to the enzyme in its anti conformation), suggesting that dA analogues with a substituent at the 2-position are likely to be better activated by human dCK.
Elucidation of Different Binding Modes of Purine Nucleosides to Human Deoxycytidine Kinase.,Sabini E, Hazra S, Konrad M, Lavie A J Med Chem. 2008 Jun 21;. PMID:18570408[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
- ↑ Sabini E, Hazra S, Konrad M, Lavie A. Elucidation of Different Binding Modes of Purine Nucleosides to Human Deoxycytidine Kinase. J Med Chem. 2008 Jun 21;. PMID:18570408 doi:10.1021/jm800134t
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