Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
Biochemistry. 2012 Sep 25;51(38):7608-17. doi: 10.1021/bi3008577. Epub 2012 Sep 14.
Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5'GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.
顺铂（CP）和奥沙利铂（OX）是广泛应用于化疗的两种铂类药物，它们在基因组 DNA 的链内鸟嘌呤（5'GG）上形成加合物。DNA 损伤识别蛋白、转录因子、错配修复蛋白和 DNA 聚合酶能够区分 CP 和 OX-GG DNA 加合物，这部分解释了 CP 和 OX 在疗效、毒性和致突变性方面的差异。此外，CP 和 OX-GG 加合物的差异识别高度依赖于 Pt-GG 加合物的序列结构。特别是，HMGB1a 结合蛋白结构域与 TGGA 序列结构中的 CP-GG DNA 加合物的结合亲和力高达 OX-GG 加合物的 53 倍，但在 AGGC 或 TGGT 序列结构中结合的差异要小得多。在这里，在三种序列结构中对 HMGB1a-Pt-DNA 复合物进行模拟，结果表明在 TGGA 序列结构中 CP-DNA 复合物的界面接触数比 OX-DNA 复合物多。然而，在 TGGT 和 AGGC 序列结构中，界面接触数相似。CP-TGGA 序列结构中更多的界面接触对应于更大的 Pt-GG 碱基对步的滚动。此外，对 HMGB1a 中苯丙氨酸 37 （Phe37）与加铂鸟嘌呤的堆积的几何分析表明，与更大的 Pt-GG 碱基对步的滚动相关的更有利的堆积模式在 TGGA 序列结构中更为常见。这些数据与我们之前的分子动力学模拟结果一致，表明 CP-TGGA 复合物能够比 OX-TGGA 复合物或 AGGC 或 TGGT 序列中的任何 CP 或 OX-DNA 复合物采样更大的滚动角。我们推断，HMGB1a 对 CP-TGGA 的高结合亲和力归因于 CP-TGGA 与 OX-TGGA 和其他 Pt-DNA 加合物相比具有更大的灵活性。这种增加的灵活性反映在 CP-TGGA 能够采样更大的滚动角，这使得 Pt-DNA 加合物与 HMGB1a 之间能够形成更多的界面接触。
