View source for 5mql


==Crystal structure of dCK mutant C3S in complex with masitinib and UDP==
<StructureSection load='5mql' size='340' side='right' caption='[[5mql]], [[Resolution|resolution]] 3.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5mql]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MQL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MQL FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DCM:2-DEOXYCYTIDINE-5-MONOPHOSPHATE'>DCM</scene>, <scene name='pdbligand=G65:Masitinib'>G65</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></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 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=5mql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mql OCA], [http://pdbe.org/5mql PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mql RCSB], [http://www.ebi.ac.uk/pdbsum/5mql PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mql ProSAT]</span></td></tr>
</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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.

Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.,Hammam K, Saez-Ayala M, Rebuffet E, Gros L, Lopez S, Hajem B, Humbert M, Baudelet E, Audebert S, Betzi S, Lugari A, Combes S, Letard S, Casteran N, Mansfield C, Moussy A, De Sepulveda P, Morelli X, Dubreuil P Nat Commun. 2017 Nov 10;8(1):1420. doi: 10.1038/s41467-017-01582-5. PMID:29127277<ref>PMID:29127277</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5mql" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Deoxycytidine kinase]]
[[Category: Audebert, S]]
[[Category: Baudelet, E]]
[[Category: Betzi, S]]
[[Category: Combes, S]]
[[Category: Dubreuil, P]]
[[Category: Gros, L]]
[[Category: Hajem, B]]
[[Category: Hammam, K]]
[[Category: Humbert, M]]
[[Category: Letard, S]]
[[Category: Lopez, S]]
[[Category: Lugari, A]]
[[Category: Mansfield, C]]
[[Category: Morelli, X]]
[[Category: Moussy, A]]
[[Category: Pez, D]]
[[Category: Rebuffet, E]]
[[Category: Saez-Ayala, M]]
[[Category: Sepulveda, P de]]
[[Category: Dck]]
[[Category: Masitinib]]
[[Category: Transferase]]