1qda
From Proteopedia
(New page: 200px<br /><applet load="1qda" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qda, resolution 1.6Å" /> '''CRYSTAL STRUCTURE OF ...) |
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| - | [[Image:1qda.gif|left|200px]]<br /><applet load="1qda" size=" | + | [[Image:1qda.gif|left|200px]]<br /><applet load="1qda" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1qda, resolution 1.6Å" /> | caption="1qda, resolution 1.6Å" /> | ||
'''CRYSTAL STRUCTURE OF EPIDOXORUBICIN-FORMALDEHYDE VIRTUAL CROSSLINK OF DNA'''<br /> | '''CRYSTAL STRUCTURE OF EPIDOXORUBICIN-FORMALDEHYDE VIRTUAL CROSSLINK OF DNA'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Epidoxorubicin and daunorubicin are proposed to be cytotoxic to tumor | + | Epidoxorubicin and daunorubicin are proposed to be cytotoxic to tumor cells by catalyzing production of formaldehyde through redox cycling and using the formaldehyde for covalent attachment to DNA at G bases. The crystal structure of epidoxorubicin covalently bound to a d(CGCGCG) oligomer was determined to 1.6 A resolution. The structure reveals slightly distorted B-form DNA bearing two molecules of epidoxorubicin symmetrically intercalated at the termini, with each covalently attached from its N3' to N2 of a G base via a CH2 group from the formaldehyde. The structure is analogous to daunorubicin covalently bound to d(CGCGCG) determined previously, except for additional hydrogen bonding from the epimeric O4' to O2 of a C base. The role of drug-DNA covalent bonding in cells was investigated with synthetic epidoxorubicin-formaldehyde conjugate (Epidoxoform) and synthetic daunorubicin-formaldehyde conjugate (Daunoform). Uptake and location of drug fluorophore in doxorubicin-resistant human breast-cancer cells (MCF-7/ADR cells) was observed by fluorescence microscopy and flow cytometry. The fluorophore of Daunoform appeared more rapidly in cells and was released more rapidly from cells than the fluorophore of Epidoxoform over a 3 h exposure period. The fluorophore appeared predominantly in the nucleus of cells treated with both conjugates. The difference in uptake is explained in terms of the slower rate of hydrolysis of Epidoxoform to the species reactive with DNA and a proposed slower release from DNA based upon the crystal structures. |
==About this Structure== | ==About this Structure== | ||
| - | 1QDA is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with DM6 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1QDA is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=DM6:'>DM6</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QDA OCA]. |
==Reference== | ==Reference== | ||
Crystal structure of epidoxorubicin-formaldehyde virtual crosslink of DNA and evidence for its formation in human breast-cancer cells., Podell ER, Harrington DJ, Taatjes DJ, Koch TH, Acta Crystallogr D Biol Crystallogr. 1999 Sep;55(Pt 9):1516-23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10489446 10489446] | Crystal structure of epidoxorubicin-formaldehyde virtual crosslink of DNA and evidence for its formation in human breast-cancer cells., Podell ER, Harrington DJ, Taatjes DJ, Koch TH, Acta Crystallogr D Biol Crystallogr. 1999 Sep;55(Pt 9):1516-23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10489446 10489446] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Harrington, D | + | [[Category: Harrington, D J.]] |
| - | [[Category: Koch, T | + | [[Category: Koch, T H.]] |
| - | [[Category: Podell, E | + | [[Category: Podell, E R.]] |
| - | [[Category: Taatjes, D | + | [[Category: Taatjes, D J.]] |
[[Category: DM6]] | [[Category: DM6]] | ||
[[Category: double helix]] | [[Category: double helix]] | ||
[[Category: drug-dna complex]] | [[Category: drug-dna complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:38:25 2008'' |
Revision as of 12:38, 21 February 2008
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CRYSTAL STRUCTURE OF EPIDOXORUBICIN-FORMALDEHYDE VIRTUAL CROSSLINK OF DNA
Overview
Epidoxorubicin and daunorubicin are proposed to be cytotoxic to tumor cells by catalyzing production of formaldehyde through redox cycling and using the formaldehyde for covalent attachment to DNA at G bases. The crystal structure of epidoxorubicin covalently bound to a d(CGCGCG) oligomer was determined to 1.6 A resolution. The structure reveals slightly distorted B-form DNA bearing two molecules of epidoxorubicin symmetrically intercalated at the termini, with each covalently attached from its N3' to N2 of a G base via a CH2 group from the formaldehyde. The structure is analogous to daunorubicin covalently bound to d(CGCGCG) determined previously, except for additional hydrogen bonding from the epimeric O4' to O2 of a C base. The role of drug-DNA covalent bonding in cells was investigated with synthetic epidoxorubicin-formaldehyde conjugate (Epidoxoform) and synthetic daunorubicin-formaldehyde conjugate (Daunoform). Uptake and location of drug fluorophore in doxorubicin-resistant human breast-cancer cells (MCF-7/ADR cells) was observed by fluorescence microscopy and flow cytometry. The fluorophore of Daunoform appeared more rapidly in cells and was released more rapidly from cells than the fluorophore of Epidoxoform over a 3 h exposure period. The fluorophore appeared predominantly in the nucleus of cells treated with both conjugates. The difference in uptake is explained in terms of the slower rate of hydrolysis of Epidoxoform to the species reactive with DNA and a proposed slower release from DNA based upon the crystal structures.
About this Structure
1QDA is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.
Reference
Crystal structure of epidoxorubicin-formaldehyde virtual crosslink of DNA and evidence for its formation in human breast-cancer cells., Podell ER, Harrington DJ, Taatjes DJ, Koch TH, Acta Crystallogr D Biol Crystallogr. 1999 Sep;55(Pt 9):1516-23. PMID:10489446
Page seeded by OCA on Thu Feb 21 14:38:25 2008
