View source for 4kcg


==Human dCK C4S-S74E mutant in complex with UDP and the DI-39 inhibitor==
<StructureSection load='4kcg' size='340' side='right'caption='[[4kcg]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4kcg]] 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=4KCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KCG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.09&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1QC:N-{2-[5-(4-{[(4,6-DIAMINOPYRIMIDIN-2-YL)SULFANYL]METHYL}-5-PROPYL-1,3-THIAZOL-2-YL)-2-METHOXYPHENOXY]ETHYL}METHANESULFONAMIDE'>1QC</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></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=4kcg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kcg OCA], [https://pdbe.org/4kcg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kcg RCSB], [https://www.ebi.ac.uk/pdbsum/4kcg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kcg ProSAT]</span></td></tr>
</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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.,Nathanson DA, Armijo AL, Tom M, Li Z, Dimitrova E, Austin WR, Nomme J, Campbell DO, Ta L, Le TM, Lee JT, Darvish R, Gordin A, Wei L, Liao HI, Wilks M, Martin C, Sadeghi S, Murphy JM, Boulos N, Phelps ME, Faull KF, Herschman HR, Jung ME, Czernin J, Lavie A, Radu CG J Exp Med. 2014 Mar 10;211(3):473-86. doi: 10.1084/jem.20131738. Epub 2014 Feb, 24. PMID:24567448<ref>PMID:24567448</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4kcg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lavie A]]
[[Category: Nomme J]]