2.4 Å crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand cross-link in a DNA dodecamer duplex
2.4 Å crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand cross-link in a DNA dodecamer duplex
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DOI：
10.1021/ic010790t
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发表时间：
2001-10-22
影响因子：
4.6
通讯作者：
Lippard, SJ
中科院分区：
文献类型：
--
作者：
Spingler, B;Whittington, DA;Lippard, SJ
(1R 2 R-二氨基环己烷）二氢铂（II）（奥沙利铂）是第三代铂抗癌化合物，其产生与顺铂相同类型的链间和链内DNA交联。奥沙利铂联合5-氟尿嘧啶最近已在欧洲、亚洲和拉丁美洲获批用于治疗转移性结直肠癌。我们在此提出了DNA十二核苷酸双链体的奥沙利铂加合物的晶体结构，该DNA十二核苷酸双链体具有与先前报道的顺铂相同的序列（Takahara，P.M.; Rosenzweig，A. C.的;弗雷德里克角，澳-地一、利帕德，S。J. Nature 1995，377，649-652）。Pt-MAD数据被用来解决铂化DNA双链体的第一个X-射线结构，该双链体来源于除顺铂之外的活性铂抗癌药物。该复合物的整体几何形状和晶体堆积（精确到2.4埃分辨率）与顺铂结构相似，尽管这两种分子在不同的空间群中结晶。{Pt（R，R-DACH）}（2+）部分的铂原子在序列5 '-d（CCTCTGGTCTCC）中的两个相邻鸟苷残基之间形成1，2-链内交联，使双螺旋向大沟弯曲近似30度。在晶格中发生端对端和端对槽的堆积相互作用。后者位于与铂交联相对的小沟中。本结构的一个新特征是在（R，R）-DACH配体的假赤道NH氢原子和铂化d（GpG）损伤的3 '-G的O 6原子之间存在氢键。这一发现为手性在介导奥沙利铂和双链体DNA之间相互作用中的重要性提供了结构证据，校准了先前发表的用于解释溶液中对映体纯邻位二胺铂络合物与DNA的反应性的模型。它还提供了一种新的手性识别之间的对映体纯的金属配合物和DNA双螺旋。
(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 Angstrom 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 similar to 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.