4q1f: Difference between revisions
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==Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 12R {N-{2-[5-(4-{(1R)-1-[(4,6-diaminopyrimidin-2-yl)sulfanyl]ethyl}-5-methyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]ethyl}methanesulfonamide}== | |||
<StructureSection load='4q1f' size='340' side='right'caption='[[4q1f]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4q1f]] 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=4Q1F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q1F 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2XN:N-{2-[5-(4-{(1R)-1-[(4,6-DIAMINOPYRIMIDIN-2-YL)SULFANYL]ETHYL}-5-METHYL-1,3-THIAZOL-2-YL)-2-METHOXYPHENOXY]ETHYL}METHANESULFONAMIDE'>2XN</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=4q1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q1f OCA], [https://pdbe.org/4q1f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q1f RCSB], [https://www.ebi.ac.uk/pdbsum/4q1f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q1f 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 == | |||
Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers. | |||
Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.,Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A J Med Chem. 2014 Oct 23. PMID:25341194<ref>PMID:25341194</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4q1f" 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]] | |||
Latest revision as of 20:26, 20 September 2023
Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 12R {N-{2-[5-(4-{(1R)-1-[(4,6-diaminopyrimidin-2-yl)sulfanyl]ethyl}-5-methyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]ethyl}methanesulfonamide}
Structural highlights
FunctionDCK_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] Publication Abstract from PubMedRecently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers. Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.,Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A J Med Chem. 2014 Oct 23. PMID:25341194[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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