5mql: Difference between revisions

Revision as of 07:26, 19 August 2020

Crystal structure of dCK mutant C3S in complex with masitinib and UDP

Structural highlights

5mql is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	DCM, G65, MG, UDP
Activity:	Deoxycytidine kinase, with EC number 2.7.1.74
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

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^[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:https://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
↑ 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. Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology. Nat Commun. 2017 Nov 10;8(1):1420. doi: 10.1038/s41467-017-01582-5. PMID:29127277 doi:https://dx.doi.org/10.1038/s41467-017-01582-5

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OCA

[1] 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:https://dx.doi.org/10.1016/j.jmb.2008.02.061

[2] 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

[3] 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. Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology. Nat Commun. 2017 Nov 10;8(1):1420. doi: 10.1038/s41467-017-01582-5. PMID:29127277 doi:https://dx.doi.org/10.1038/s41467-017-01582-5

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==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=''>
+<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>
+<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://proteopedia.org/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>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/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 ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5mql" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Deoxycytidine kinase 3D structures|Deoxycytidine kinase 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[Category: Deoxycytidine kinase]]
+[[Category: Large Structures]]
 [[Category: Audebert, S]]
 [[Category: Baudelet, E]]

5mql: Difference between revisions

Revision as of 07:26, 19 August 2020

Crystal structure of dCK mutant C3S in complex with masitinib and UDP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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