1al9
From Proteopedia
(New page: 200px<br /><applet load="1al9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1al9" /> '''NMR STUDY OF DNA (5'-D(*AP*CP*GP*TP*AP*CP*GP...) |
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| - | [[Image:1al9.gif|left|200px]]<br /><applet load="1al9" size=" | + | [[Image:1al9.gif|left|200px]]<br /><applet load="1al9" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1al9" /> | caption="1al9" /> | ||
'''NMR STUDY OF DNA (5'-D(*AP*CP*GP*TP*AP*CP*GP*T)-3') SELF-COMPLEMENTARY DUPLEX COMPLEXED WITH A BIS-DAUNORUBICIN, MINIMIZED AVERAGE STRUCTURE'''<br /> | '''NMR STUDY OF DNA (5'-D(*AP*CP*GP*TP*AP*CP*GP*T)-3') SELF-COMPLEMENTARY DUPLEX COMPLEXED WITH A BIS-DAUNORUBICIN, MINIMIZED AVERAGE STRUCTURE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In the search for new generations of anthracycline drugs, lower cytotoxic | + | In the search for new generations of anthracycline drugs, lower cytotoxic side effects and higher activity against resistant cancer cells are two major goals. A new class of bis-intercalating anthracycline drugs has been designed, synthesized, and shown to have promising activity against multidrug-resistant cells. Two daunorubicins symmetrically linked together via a p-xylenyl group, either at their N3' (compound WP631) or N4' sites (compound WP652), exhibit extraordinary DNA binding affinities. We have used high-resolution NRM studies to understand the DNA binding mode of these two new bis-daunorubicin anticancer compounds. The structures of the WP631-d(ACGTACGT)2 and the WP652-d(TGTACA)2 complexes have been determined by NOE-restrained refinement. WP631 binds strongly to the 5'-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated between the two CpG sites at both ends of the hexanucleotide sequence. The overall conformation of the WP631-d(CGTACG)2 part is remarkably similar to the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG)2, as predicted previously [Gao, Y.-G., & Wang, A.H.H. (1996), J. Biomol. Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652 prefers the 5'-PyGTPu tetranucleotide sequence, with the aglycons intercalated between the PypG and TpPu sites. The binding of WP652 to DNA results in a severely distroted B-DNA duplex with the p-xylenyl tether moiety significantly protruded away from the bottom of the minor groove. While WP652 in some ways behaves similarly to other anticancer bis-intercalating antibiotics (e.g., triostine A and echinomycin), the detailed interactions between those two classes of bis-intercalators are quite different. |
==About this Structure== | ==About this Structure== | ||
| - | 1AL9 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with BDA as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1AL9 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=BDA:'>BDA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AL9 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Robinson, H.]] | [[Category: Robinson, H.]] | ||
| - | [[Category: Wang, A | + | [[Category: Wang, A H.J.]] |
[[Category: BDA]] | [[Category: BDA]] | ||
[[Category: bis-intercalator]] | [[Category: bis-intercalator]] | ||
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[[Category: dna]] | [[Category: dna]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:45:48 2008'' |
Revision as of 09:45, 21 February 2008
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NMR STUDY OF DNA (5'-D(*AP*CP*GP*TP*AP*CP*GP*T)-3') SELF-COMPLEMENTARY DUPLEX COMPLEXED WITH A BIS-DAUNORUBICIN, MINIMIZED AVERAGE STRUCTURE
Overview
In the search for new generations of anthracycline drugs, lower cytotoxic side effects and higher activity against resistant cancer cells are two major goals. A new class of bis-intercalating anthracycline drugs has been designed, synthesized, and shown to have promising activity against multidrug-resistant cells. Two daunorubicins symmetrically linked together via a p-xylenyl group, either at their N3' (compound WP631) or N4' sites (compound WP652), exhibit extraordinary DNA binding affinities. We have used high-resolution NRM studies to understand the DNA binding mode of these two new bis-daunorubicin anticancer compounds. The structures of the WP631-d(ACGTACGT)2 and the WP652-d(TGTACA)2 complexes have been determined by NOE-restrained refinement. WP631 binds strongly to the 5'-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated between the two CpG sites at both ends of the hexanucleotide sequence. The overall conformation of the WP631-d(CGTACG)2 part is remarkably similar to the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG)2, as predicted previously [Gao, Y.-G., & Wang, A.H.H. (1996), J. Biomol. Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652 prefers the 5'-PyGTPu tetranucleotide sequence, with the aglycons intercalated between the PypG and TpPu sites. The binding of WP652 to DNA results in a severely distroted B-DNA duplex with the p-xylenyl tether moiety significantly protruded away from the bottom of the minor groove. While WP652 in some ways behaves similarly to other anticancer bis-intercalating antibiotics (e.g., triostine A and echinomycin), the detailed interactions between those two classes of bis-intercalators are quite different.
About this Structure
1AL9 is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.
Reference
Binding of two novel bisdaunorubicins to DNA studied by NMR spectroscopy., Robinson H, Priebe W, Chaires JB, Wang AH, Biochemistry. 1997 Jul 22;36(29):8663-70. PMID:9289011
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