1IHH

2.4 ANGSTROM CRYSTAL STRUCTURE OF AN OXALIPLATIN 1,2-D(GPG) INTRASTRAND CROSS-LINK IN A DNA DODECAMER DUPLEX

1IHH の概要

• エントリーDOI: 10.2210/pdb1ihh/pdb
• 分子名称: 5'-D(*CP*CP*TP*CP*TP*GP*GP*TP*CP*TP*CP*C)-3', 5'-D(*GP*GP*AP*GP*AP*CP*CP*AP*GP*AP*GP*G)-3', PLATINUM (II) ION, ... (6 entities in total)
• 機能のキーワード: right handed dna, double helix, complexed with drug, oxaliplatin, modified, deoxynucleic acid, dna
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 7773.38

構造登録者

Spingler, B.,Whittington, D.A.,Lippard, S.J. (登録日: 2001-04-19, 公開日: 2001-10-26, 最終更新日: 2024-02-07)

主引用文献

Spingler, B.,Whittington, D.A.,Lippard, S.J.
2.4 A crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand cross-link in a DNA dodecamer duplex.
Inorg.Chem., 40:5596-5602, 2001

PubMed Abstract: (1R,2R-Diaminocyclohexane)oxalatoplatinum(II) (oxaliplatin) is a third-generation platinum anticancer compound that produces the same type of inter- and intrastrand DNA cross-links as cisplatin. In combination with 5-fluorouracil, oxaliplatin has been recently approved in Europe, Asia, and Latin America for the treatment of metastatic colorectal cancer. We present here the crystal structure of an oxaliplatin adduct of a DNA dodecanucleotide duplex having the same sequence as that previously reported for cisplatin (Takahara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Nature 1995, 377, 649-652). Pt-MAD data were used to solve this first X-ray structure of a platinated DNA duplex derived from an active platinum anticancer drug other than cisplatin. The overall geometry and crystal packing of the complex, refined to 2.4 A resolution, are similar to those of the cisplatin structure, despite the fact that the two molecules crystallize in different space groups. The platinum atom of the [Pt(R,R-DACH)](2+) moiety forms a 1,2-intrastrand cross-link between two adjacent guanosine residues in the sequence 5'-d(CCTCTGGTCTCC), bending the double helix by approximately 30 degrees toward the major groove. Both end-to-end and end-to-groove packing interactions occur in the crystal lattice. The latter is positioned in the minor groove opposite the platinum cross-link. A novel feature of the present structure is the presence of a hydrogen bond between the pseudoequatorial NH hydrogen atom of the (R,R)-DACH ligand and the O6 atom of the 3'-G of the platinated d(GpG) lesion. This finding provides structural evidence for the importance of chirality in mediating the interaction between oxaliplatin and duplex DNA, calibrating previously published models used to explain the reactivity of enantiomerically pure vicinal diamine platinum complexes with DNA in solution. It also provides a new kind of chiral recognition between an enantiomerically pure metal complex and the DNA double helix.

PubMed: 11599959
DOI: 10.1021/ic010790t

実験手法

X-RAY DIFFRACTION (2.4 Å)