Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.
Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.
复制标题
咪唑-咪唑对作为 T:G 错配碱基对的小沟识别基序。
DOI：
10.1093/nar/27.21.4183
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发表时间：
1999
影响因子：
14.9
通讯作者：
Wang,AH
中科院分区：
文献类型：
--
作者：
Yang,XL;Hubbard,RB;Lee,M;Tao,ZF;Sugiyama,H;Wang,AH
T:G错配碱基对与许多基因突变有关。通过研究由T:G碱基对引起的DNA结构扰动以及使用小分子配体对不匹配进行特异性探测，可以帮助理解其生物学后果。我们之前已经证明AR-1-144，一个三咪唑（Im-lm-lm）小凹槽结合剂，识别序列CCGG。对AR-1-144和GAAC-CGGTTC对称2:1配合物的核磁共振结构分析表明，每个AR-1-144与四个碱基对结合，鸟嘌呤N2氨基与并排的lm/lm对形成分叉氢键。我们预测在T:G摆动碱基对中游离的G- n2氨基可以形成两个单独的氢键并形成并排的lm/lm对。因此，lm/lm对可能是DNA中T:G碱基对的良好识别基序。AR-1-144同型二聚体与GAACTGGTTC紧密结合，可以通过二维NOE NMR精细化进行详细的结构分析，精细化的结构证实了我们的预测。令人惊讶的是，AR-1-144不与GAATCG-GTTC结合。研究进一步表明，lm-lm-lm/lm-Py-lm异二聚体和lm-lm-lm/lm-lm-lm -lm同二聚体与CACGGGTC + GACICGTG双链结合较强。这些结果共同表明，lm/lm对可以专门识别单个T:G不匹配。我们的结果可能对未来设计分子（例如连接二聚体）有用，这些分子可以特异性地识别单个T:G不匹配。
The T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences may be aided by studying the structural perturbation of DNA caused by a T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown previously that AR-1-144, a tri-imidazole (Im-lm-lm) minor groove binder, recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1 complex of AR-1-144 and GAAC-CGGTTC revealed that each AR-1-144 binds to four base pairs with the guanine N2 amino group forming a bifurcated hydrogen bond to a side-by-side lm/lm pair. We predicted that the free G-N2 amino group in a T:G wobble base pair can form twoindividualhydrogen bonds to a side-by-side lm/lm pair. Thus an lm/lm pair may be a good recognition motif for a T:G base pair in DNA. Cooperative and tight binding of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural analysis by 2D NOE NMR refinement and the refined structure confirms our prediction. Surprisingly, AR-1-144 does not bind to GAATCG-GTTC. We further show that both the lm-lm-lm/lm-Py-lm heterodimer and the lm-lm-lm/lm-lm-lm homodimer bind strongly to the CACGGGTC + GACICGTG duplex. These results together suggest that an lm/lm pair can specifically recognize a single T:G mismatch. Our results may be useful in future design of molecules (e.g. linked dimers) that can recognize a single T:G mismatch with specificity.