THE MOLECULAR-ORIGIN OF DNA DRUG SPECIFICITY IN NETROPSIN AND DISTAMYCIN
THE MOLECULAR-ORIGIN OF DNA DRUG SPECIFICITY IN NETROPSIN AND DISTAMYCIN
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DOI：
10.1073/pnas.82.5.1376
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发表时间：
1985-01-01
影响因子：
11.1
通讯作者：
DICKERSON, RE
中科院分区：
文献类型：
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作者：
KOPKA, ML;YOON, C;DICKERSON, RE
对netropsin与B-DNA十二聚体序列C-G-C-G-A-A-T-T-BrC-G-C-G - g复合物的x射线分析表明，抗肿瘤抗生素通过取代水合脊柱的水分子在小凹槽内结合。Netropsin amide NH提供H键来连接DNA腺嘌呤N-3和胸腺嘧啶O-2原子，这些原子发生在相邻的碱基对和相反的螺旋链上，就像水合作用的脊柱一样。凹槽的狭窄迫使嗜netropsin分子对称地位于中心，其2个吡咯环稍微不共面，因此每个环与凹槽各自区域的壁平行。药物结合既不能解开也不能拉长双螺旋，但它确实迫使小凹槽打开0.5-2.0 ang。，螺旋轴向后弯曲8度。跨越依恋区域。嗜netropsin分子有一个固有的扭曲，有利于插入到B-DNA的小凹槽中，并且在结合时它被赋予一个小的额外扭曲。使netropsin优先结合4个或更多A .cntdot的碱基特异性。T碱基对不是由氢键提供的，而是由腺嘌呤C-2氢和药物分子吡咯环上的CH基团之间紧密的范德华接触提供的。咪唑取代1个或多个吡咯可以识别G .cntdot。C碱基对也是如此，它可能导致一类合成的lexitropsins，能够读取任何所需的DNA碱基对短序列。
X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-T-BrC-G-C-G reveals that the antitumor antibiotic binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish H bonds to bridge DNA adenine N-3 and thymine O-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its 2 pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 .ANG., and it bends back the helix axis by 8.degree. across the region of attachment. The netropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of 4 or more A .cntdot. T base pairs is provided not by H bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of 1 or more pyrroles by imidazole could permit recognition of G .cntdot. C base pairs as well, and it could lead to a class of synthetic lexitropsins, capable of reading any desired short sequence of DNA base pairs.