1p60
From Proteopedia
(New page: 200px<br /> <applet load="1p60" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p60, resolution 1.96Å" /> '''Structure of human ...) |
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caption="1p60, resolution 1.96Å" /> | caption="1p60, resolution 1.96Å" /> | ||
'''Structure of human dCK complexed with 2'-Deoxycytidine and ADP, Space group C 2 2 21'''<br /> | '''Structure of human dCK complexed with 2'-Deoxycytidine and ADP, Space group C 2 2 21'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Human deoxycytidine kinase (dCK) phosphorylates the natural | + | Human deoxycytidine kinase (dCK) phosphorylates the natural deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of numerous nucleoside analog prodrugs routinely used in cancer and antiviral chemotherapy. For many of these compounds, the phosphorylation step catalyzed by dCK is the rate-limiting step in their overall activation pathway. To determine the factors that limit the phosphorylation efficiency of the prodrug, we solved the crystal structure of dCK to a resolution of 1.6 A in complex with its physiological substrate deoxycytidine and with the prodrugs AraC and gemcitabine. The structures reveal the determinants of dCK substrate specificity. Especially relevant to new prodrug development is the interaction between Arg128 and the hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and gemcitabine. On the basis of the structures, we designed a catalytically superior dCK variant that could be used in suicide gene-therapy applications. |
==About this Structure== | ==About this Structure== | ||
| - | 1P60 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ADP and DCZ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1P60 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ADP:'>ADP</scene> and <scene name='pdbligand=DCZ:'>DCZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1P60 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: p-loop]] | [[Category: p-loop]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:25:31 2008'' |
Revision as of 12:25, 21 February 2008
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Structure of human dCK complexed with 2'-Deoxycytidine and ADP, Space group C 2 2 21
Overview
Human deoxycytidine kinase (dCK) phosphorylates the natural deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of numerous nucleoside analog prodrugs routinely used in cancer and antiviral chemotherapy. For many of these compounds, the phosphorylation step catalyzed by dCK is the rate-limiting step in their overall activation pathway. To determine the factors that limit the phosphorylation efficiency of the prodrug, we solved the crystal structure of dCK to a resolution of 1.6 A in complex with its physiological substrate deoxycytidine and with the prodrugs AraC and gemcitabine. The structures reveal the determinants of dCK substrate specificity. Especially relevant to new prodrug development is the interaction between Arg128 and the hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and gemcitabine. On the basis of the structures, we designed a catalytically superior dCK variant that could be used in suicide gene-therapy applications.
About this Structure
1P60 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Deoxycytidine kinase, with EC number 2.7.1.74 Full crystallographic information is available from OCA.
Reference
Structure of human dCK suggests strategies to improve anticancer and antiviral therapy., Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A, Nat Struct Biol. 2003 Jul;10(7):513-9. PMID:12808445
Page seeded by OCA on Thu Feb 21 14:25:31 2008
Categories: Deoxycytidine kinase | Homo sapiens | Single protein | Konrad, M. | Lavie, A. | Monnerjahn, C. | Ort, S. | Sabini, E. | ADP | DCZ | Deoxycytidine | Nucleoside kinase | P-loop
