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| | {{STRUCTURE_1dl8| PDB=1dl8 | SCENE= }} | | {{STRUCTURE_1dl8| PDB=1dl8 | SCENE= }} |
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| - | '''CRYSTAL STRUCTURE OF 5-F-9-AMINO-(N-(2-DIMETHYLAMINO)ETHYL)ACRIDINE-4-CARBOXAMIDE BOUND TO D(CGTACG)2'''
| + | ===CRYSTAL STRUCTURE OF 5-F-9-AMINO-(N-(2-DIMETHYLAMINO)ETHYL)ACRIDINE-4-CARBOXAMIDE BOUND TO D(CGTACG)2=== |
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| - | ==Overview==
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| - | For a series of antitumor-active 5-substituted 9-aminoacridine-4-carboxamide topoisomerase II poisons, we have used X-ray crystallography and stopped-flow spectrophotometry to explore relationships between DNA binding kinetics, biological activity, and the structures of their DNA complexes. The structure of 5-F-9-amino-[N-(2-dimethylamino)ethyl]-acridine-4-carboxamide bound to d(CGTACG)(2) has been solved to a resolution of 1.55 A in space group P6(4). A drug molecule intercalates between each of the CpG dinucleotide steps, its protonated dimethylamino group partially occupying positions close to the N7 and O6 atoms of guanine G2 in the major groove. A water molecule forms bridging hydrogen bonds between the 4-carboxamide NH and the phosphate group of the same guanine. Intercalation unwinds steps 1 and 2 by 12 degrees and 8 degrees, respectively compared with B-DNA, whereas the central TpA step is overwound by 10 degrees. Nonphenyl 5-substituents, on average, decrease mean DNA dissociation rates by a factor of three, regardless of their steric, hydrophobic, H-bonding, or electronic properties. Cytotoxicity is enhanced on average 4-fold and binding affinities rise by 3-fold, thus there is an apparent association between kinetics, affinity, and cytotoxicity. Taken together, the structural and kinetic studies imply that the main origin of this association is enhanced stacking interactions between the 5-substituent and cytosine in the CpG binding site. Ligand-dependent perturbations in base pair twist angles and their consequent effects on base pair-base pair stacking interactions may also contribute to the stability of the intercalated complex. 5-Phenyl substituents modify dissociation rates without affecting affinities, and variations in their biological activity are not correlated with DNA binding properties, which suggests that they interact directly with the topoisomerase protein.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10953060}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10953060 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10953060}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Dna]] | | [[Category: Dna]] |
| | [[Category: Intercalation]] | | [[Category: Intercalation]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:58:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 23:14:29 2008'' |
Revision as of 20:14, 30 June 2008
Template:STRUCTURE 1dl8
CRYSTAL STRUCTURE OF 5-F-9-AMINO-(N-(2-DIMETHYLAMINO)ETHYL)ACRIDINE-4-CARBOXAMIDE BOUND TO D(CGTACG)2
Template:ABSTRACT PUBMED 10953060
About this Structure
Full crystallographic information is available from OCA.
Reference
Acridinecarboxamide topoisomerase poisons: structural and kinetic studies of the DNA complexes of 5-substituted 9-amino-(N-(2-dimethylamino)ethyl)acridine-4-carboxamides., Adams A, Guss JM, Collyer CA, Denny WA, Prakash AS, Wakelin LP, Mol Pharmacol. 2000 Sep;58(3):649-58. PMID:10953060
Page seeded by OCA on Mon Jun 30 23:14:29 2008
