2no9: Difference between revisions
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==The structure of deoxycytidine kinase complexed with troxacitabine and ADP.== | ==The structure of deoxycytidine kinase complexed with troxacitabine and ADP.== | ||
<StructureSection load='2no9' size='340' side='right'caption='[[2no9]]' scene=''> | <StructureSection load='2no9' size='340' side='right'caption='[[2no9]], [[Resolution|resolution]] 2.15Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NO9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NO9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[2no9]] is a 2 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=2NO9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NO9 FirstGlance]. <br> | ||
</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=2no9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2no9 OCA], [https://pdbe.org/2no9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2no9 RCSB], [https://www.ebi.ac.uk/pdbsum/2no9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2no9 ProSAT]</span></td></tr> | </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=LTT:4-AMINO-1-[(2S,4S)-2-(HYDROXYMETHYL)-1,3-DIOXOLAN-4-YL]PYRIMIDIN-2(1H)-ONE'>LTT</scene></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]], [[2a2z|2a2z]], [[2a30|2a30]], [[2no0|2no0]], [[2no1|2no1]], [[1no6|1no6]], [[2no7|2no7]], [[2noa|2noa]]</div></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=2no9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2no9 OCA], [https://pdbe.org/2no9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2no9 RCSB], [https://www.ebi.ac.uk/pdbsum/2no9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2no9 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== 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> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2no9 ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2no9 ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class. | |||
Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase.,Sabini E, Hazra S, Konrad M, Burley SK, Lavie A Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:17158155<ref>PMID:17158155</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2no9" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]] | *[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Deoxycytidine kinase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lavie A]] | [[Category: Lavie, A]] | ||
[[Category: Sabini E]] | [[Category: Sabini, E]] | ||
[[Category: Anticancer]] | |||
[[Category: Dck]] | |||
[[Category: Enantiomer]] | |||
[[Category: Human deoxycytidine kinase]] | |||
[[Category: L-dc]] | |||
[[Category: Transferase]] | |||
[[Category: Troxacitabine]] | |||
Revision as of 21:06, 20 October 2021
The structure of deoxycytidine kinase complexed with troxacitabine and ADP.The structure of deoxycytidine kinase complexed with troxacitabine 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 PubMedL-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class. Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase.,Sabini E, Hazra S, Konrad M, Burley SK, Lavie A Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:17158155[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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