NMR and Molecular Modeling Studies of the Interaction of Artificial AP Lyases with a DNA Duplex Containing an Apurinic Abasic Site Model
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- 作者：Yannick Coppel ; Jean-Franç ; ois Constant ; Christian Coulombeau ; Martine Demeunynck ; Julian Garcia ; and Jean Lhomme
- 刊名：Biochemistry
- 出版年：1997
- 出版时间：April 22, 1997
- 年：1997
- 卷：36
- 期：16
- 页码：4831 - 4843
- 全文大小：814K
- 年卷期：v.36,no.16(April 22, 1997)
- ISSN：1520-4995
文摘
Tailor-made molecules, DTAc and ATAc, that incorporate a nucleicbase (adenine or 2,6-diaminopurine) linked by a diamino chain to an intercalator(9-amino-6-chloro-2-methoxyacridine)selectively recognize and efficiently cleave abasic sites in DNAvia a 
-elimination reaction. The three-dimensional structure of the complexes of DTAc and ATAc bound to a DNAundecamer, the5'd(C1G2C3A4C5X6C7A8C9G10C11)3'·3'd(G22C21G20T19G18T17G16T15G14C13G12)5'duplex in which the Xresidue is a stable abasic site[3-hydroxy-2-(hydroxymethyl)tetrahydrofuran], has been studiedby combinedNMR-energy minimization methods. Analysis of the NMR spectrareveals that DTAc and ATAc interactwith a very similar fashion and form two different complexes with DNA,present in a ratio of 70/30(±10). In both complexes, the acridine ring intercalatesexclusively between the C3·G20 and A4·T19base pairs, the linker is located in the minor groove, and the basemoiety docks in the abasic site. Theprincipal difference between the major and the minor complexes consistsof a 180
rotation of the acridinering around the Acr-C-N bond within the same intercalation site.Molecular modeling studies withfew intermolecular ligand-DNA restraints were used to investigate thegeometry of the base pair formedbetween the diaminopurine of DTAc and the T17 ring. The mostenergetically favored complex has the2,6-diaminopurine of DTAc base paired with the T17 ring in a Hoogsteenconformation. The modelsDTAc and ATAc are also discussed as nuclease mimics and cleaving agentsat abasic sites.
-elimination reaction. The three-dimensional structure of the complexes of DTAc and ATAc bound to a DNAundecamer, the5'd(C1G2C3A4C5X6C7A8C9G10C11)3'·3'd(G22C21G20T19G18T17G16T15G14C13G12)5'duplex in which the Xresidue is a stable abasic site[3-hydroxy-2-(hydroxymethyl)tetrahydrofuran], has been studiedby combinedNMR-energy minimization methods. Analysis of the NMR spectrareveals that DTAc and ATAc interactwith a very similar fashion and form two different complexes with DNA,present in a ratio of 70/30(±10). In both complexes, the acridine ring intercalatesexclusively between the C3·G20 and A4·T19base pairs, the linker is located in the minor groove, and the basemoiety docks in the abasic site. Theprincipal difference between the major and the minor complexes consistsof a 180 rotation of the acridinering around the Acr-C-N bond within the same intercalation site.Molecular modeling studies withfew intermolecular ligand-DNA restraints were used to investigate thegeometry of the base pair formedbetween the diaminopurine of DTAc and the T17 ring. The mostenergetically favored complex has the2,6-diaminopurine of DTAc base paired with the T17 ring in a Hoogsteenconformation. The modelsDTAc and ATAc are also discussed as nuclease mimics and cleaving agentsat abasic sites.