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4q1e

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Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 10 {2-{[(1R/S)-1-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]-5-methyl-1,3-thiazol 4-yl}ethyl]sulfanyl}pyrimidine-4,6-diamine}

Structural highlights

4q1e is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sabini E, Hazra S, Ort S, Konrad M, Lavie A. Structural basis for substrate promiscuity of dCK. J Mol Biol. 2008 May 2;378(3):607-21. Epub 2008 Mar 3. PMID:18377927 doi:http://dx.doi.org/10.1016/j.jmb.2008.02.061
↑ Hazra S, Ort S, Konrad M, Lavie A. Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues . Biochemistry. 2010 Aug 10;49(31):6784-90. PMID:20614893 doi:10.1021/bi100839e
↑ 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. Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability. J Med Chem. 2014 Oct 23. PMID:25341194 doi:http://dx.doi.org/10.1021/jm501124j

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4q1e"

Categories: Homo sapiens | Large Structures | Lavie A | Nomme J

@@ Line 3: / Line 3: @@
 <StructureSection load='4q1e' size='340' side='right'caption='[[4q1e]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4q1e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q1E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4q1e]] 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=4Q1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q1E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2Y7:(S)-2-((1-(2-(3-(2-FLUOROETHOXY)-4-METHOXYPHENYL)-5-METHYLTHIAZOL-4-YL)ETHYL)THIO)PYRIMIDINE-4,6-DIAMINE'>2Y7</scene>, <scene name='pdbligand=2Y8:(R)-2-((1-(2-(3-(2-FLUOROETHOXY)-4-METHOXYPHENYL)-5-METHYLTHIAZOL-4-YL)ETHYL)THIO)PYRIMIDINE-4,6-DIAMINE'>2Y8</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4q18|4q18]], [[4q19|4q19]], [[4q1a|4q1a]], [[4q1b|4q1b]], [[4q1c|4q1c]], [[4q1d|4q1d]], [[4q1f|4q1f]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2Y7:(S)-2-((1-(2-(3-(2-FLUOROETHOXY)-4-METHOXYPHENYL)-5-METHYLTHIAZOL-4-YL)ETHYL)THIO)PYRIMIDINE-4,6-DIAMINE'>2Y7</scene>, <scene name='pdbligand=2Y8:(R)-2-((1-(2-(3-(2-FLUOROETHOXY)-4-METHOXYPHENYL)-5-METHYLTHIAZOL-4-YL)ETHYL)THIO)PYRIMIDINE-4,6-DIAMINE'>2Y8</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></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 HUMAN])</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=4q1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q1e OCA], [https://pdbe.org/4q1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q1e RCSB], [https://www.ebi.ac.uk/pdbsum/4q1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q1e ProSAT]</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 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=4q1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q1e OCA], [http://pdbe.org/4q1e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q1e RCSB], [http://www.ebi.ac.uk/pdbsum/4q1e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q1e 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>
+[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 ==
@@ Line 23: / Line 21: @@
 ==See Also==
-*[[Deoxycytidine kinase|Deoxycytidine kinase]]
+*[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Deoxycytidine kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Lavie, A]]
+[[Category: Lavie A]]
-[[Category: Nomme, J]]
+[[Category: Nomme J]]
-[[Category: Deoxycytidine]]
-[[Category: Inhibitor complex]]
-[[Category: Kinase]]
-[[Category: Phosphoryl transfer]]
-[[Category: Phosphorylation]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

4q1e

From Proteopedia

Current revision

Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 10 {2-{[(1R/S)-1-{2-[3-(2-fluoroethoxy)-4-methoxyphenyl]-5-methyl-1,3-thiazol 4-yl}ethyl]sulfanyl}pyrimidine-4,6-diamine}

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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