2a7q: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2a7q]] is a 1 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A7Q FirstGlance]. <br> | <table><tr><td colspan='2'>[[2a7q]] is a 1 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A7Q FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1p5z|1p5z]], [[1p60|1p60]], [[1p61|1p61]], [[1p62|1p62]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1p5z|1p5z]], [[1p60|1p60]], [[1p61|1p61]], [[1p62|1p62]]</td></tr> | ||
<tr><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 Homo sapiens])</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 Homo sapiens])</td></tr> | ||
<tr><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> | <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> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2a7q RCSB], [http://www.ebi.ac.uk/pdbsum/2a7q PDBsum]</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=2a7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2a7q RCSB], [http://www.ebi.ac.uk/pdbsum/2a7q PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== 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> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Deoxycytidine kinase]] | [[Category: Deoxycytidine kinase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Ealick, S E | [[Category: Ealick, S E]] | ||
[[Category: III, J A.Secrist | [[Category: III, J A.Secrist]] | ||
[[Category: Zhang, Y | [[Category: Zhang, Y]] | ||
[[Category: Alpha/beta parallel beta-sheet of 5 strand]] | [[Category: Alpha/beta parallel beta-sheet of 5 strand]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 05:58, 25 December 2014
Crystal structure of human dCK complexed with clofarabine and ADPCrystal structure of human dCK complexed with clofarabine and ADP
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 PubMedClofarabine [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 AlsoReferences
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