REFINEMENT OF NETROPSIN BOUND TO DNA - BIAS AND FEEDBACK IN ELECTRON-DENSITY MAP INTERPRETATION
REFINEMENT OF NETROPSIN BOUND TO DNA - BIAS AND FEEDBACK IN ELECTRON-DENSITY MAP INTERPRETATION
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DOI：
10.1021/bi00015a009
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发表时间：
1995-04-18
期刊：
影响因子：
2.9
通讯作者：
DICKERSON, RE
中科院分区：
文献类型：
--
作者：
GOODSELL, DS;KOPKA, ML;DICKERSON, RE
重新检查了 B-DNA 十二聚体 CGCGAATTCGCG 与抗肿瘤药物 netropsin 复合物的 X 射线晶体结构，以准确定位药物以进行基于计算机的药物设计。最佳解决方案是将药物集中在小沟的 AATT 区域，沿着沟底与腺嘌呤 N3 和胸腺嘧啶 O2 原子形成三个良好的分叉氢键。 netropsin 的吡咯环紧靠腺嘌呤的 C2 位置堆积，没有为鸟嘌呤的胺基留下空间，因此为 A 提供了结构原理。 netropsin 的 T 特异性。另一种定位是药物沿着小凹槽移动约。根据自由 R 因子计算和原始无药物差异图的出现，拒绝二分之一碱基对步骤。最终省略图虽然外观更令人愉悦，但并不是区分正确和错误结构的可靠方法。移动的替代药物位置忽略了沿着凹槽底部的潜在氢键，没有为 netropsin 观察到的 A 提供解释。 T 特异性，并且与 NMR 结果相矛盾 [Patel, D. J. (1982) Proc.国家。阿卡德。科学。美国 79, 6424]。
The X-ray crystal structure of the complex of the B-DNA dodecamer CGCGAATTCGCG with the antitumor drug netropsin has been reexamined to locate the drug accurately for computer-based drug design. The optimum solution is with the drug centered in the AATT region of the minor groove, making three good bifurcated hydrogen bonds with adenine N3 and thymine O2 atoms along the floor of the groove. Pyrrole rings of netropsin are packed against the C2 positions of adenines, leaving no room for the amine group of guanine and, hence, providing a structural rationale for the A . T specificity of netropsin. An alternative positioning in which the drug is shifted along the minor groove by ca. one-half base pair step is rejected on the basis of free R factor calculations and the appearance of the original drug-free difference maps. Final omit maps, although of more pleasing appearance, are not a dependable means of discriminating between right and wrong structures. The shifted alternative drug position ignores potential hydrogen bonding along the floor of the groove, provides no explanation for netropsin's observed A . T specificity, and is contradicted by NMR results [Patel, D. J. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 6424].