SEQUENCE SPECIFICITY OF QUINOXALINE ANTIBIOTICS .1. SOLUTION STRUCTURE OF A 1/1-COMPLEX BETWEEN TRIOSTIN A AND [D(GACGTC)](2) AND COMPARISON WITH THE SOLUTION STRUCTURE OF THE [N-MECYS(3),N-MECYS(7)]TANDEM-[D(GATATC)](2) COMPLEX
SEQUENCE SPECIFICITY OF QUINOXALINE ANTIBIOTICS .1. SOLUTION STRUCTURE OF A 1/1-COMPLEX BETWEEN TRIOSTIN A AND [D(GACGTC)](2) AND COMPARISON WITH THE SOLUTION STRUCTURE OF THE [N-MECYS(3),N-MECYS(7)]TANDEM-[D(GATATC)](2) COMPLEX
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DOI：
10.1021/bi00207a005
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发表时间：
1994-10-18
期刊：
影响因子：
2.9
通讯作者：
FEIGON, J
中科院分区：
文献类型：
--
作者：
ADDESS, KJ;FEIGON, J
Triostin A是一种天然存在的喹喔啉抗生素，在缬氨酸和半胱氨酸残基上含有N-甲基，在NCGN位点与DNA序列特异性结合。[N-MeCys（3），N-MeCys（7）]TANDEM（CysMeTANDEM）是一种合成喹喔啉抗生素，其化学结构与triostin A的不同之处仅在于不含N-甲基取代基的缬氨酸残基。CysMeTANDEM具有不同于triostin A的序列特异性，在NTAN位点特异性结合DNA。为了理解决定这些喹喔啉抗生素的序列特异性的因素，使用NMR衍生的距离和二面角限制确定了Triostin A与DNA六聚体[d（GACGTC）]（2）的1：1复合物的溶液结构。将曲骨菌素A-[d（GACGTC）]（2）复合物的溶液结构直接与CysMeTANDEM与[d（GATATC）]（2）的1：1复合物的溶液结构进行比较，并且还与曲骨菌素A与[d（CGTACG）]（2）的2：1复合物的晶体结构进行比较。Triostin A与[d（GACGTC）]（2）结合，作为CpG步骤周围的双嵌入剂，药物的肽环结合在DNA的小沟中。该复合物的中心C.G碱基对以近似-9.0度的平均螺旋扭曲角下旋，并向内弯曲约25度。在CpG结合位点的每个Ala NH和GN 3质子之间存在分子间氢键。在CysMeTANDEM-[d（GATATC）]（2）配合物的溶液结构中观察到类似的结构特征。然而，在triostin A-[d（GACGTC）]（2）复合物的结构中，观察到药物的每个Ala CO氧与鸟嘌呤的2-氨基质子之间的两个分子间氢键。这些氢键在CysMeTANDEM-DNA复合物中不形成。相反，CysMeTANDEM在Ala CO原子和瓦尔酰胺质子之间含有两个分子内氢键，使得Ala CO原子不能形成两个分子间氢键。讨论了这些分子间氢键在Triostin A的CpG特异性中的作用。
Triostin A, a naturally occurring quinoxaline antibiotic that contains N-methyl groups on the valine and cysteine residues, binds sequence specifically to DNA at NCGN sites. [N-MeCys(3),N-MeCys(7)]TANDEM (CysMeTANDEM), a synthetic quinoxaline antibiotic, differs in its chemical structure from triostin A only at the valine residues, which contain no N-methyl substituents. CysMeTANDEM has a sequence specificity different from triostin A, binding specifically to DNA at NTAN sites. To understand the factors that determine the sequence specificity of these quinoxaline antibiotics, the solution structure of a 1:1 complex of triostin A with the DNA hexamer [d(GACGTC)](2) has been determined using NMR-derived distance and dihedral angle restraints. The solution structure of the triostin A-[d(GACGTC)](2) complex is compared directly to the solution structure of a 1:1 complex of CysMeTANDEM with [d(GATATC)](2) and is also compared to the crystal structure of 2:1 complex of triostin A with [d(CGTACG)](2). Triostin A binds to [d(GACGTC)](2) as a bis-intercalator around the CpG step, and the peptide ring of the drug binds in the minor groove of the DNA. The central C.G base pairs of the complex are underwound with an average helical twist angle of similar to-9.0 degrees and buckle inward by about 25 degrees. There are intermolecular hydrogen bonds between each of the Ala NH and the GN3 protons of the CpGbinding site. Similar structural features are observed in t he solution structure of the CysMeTANDEM-[d(GATATC)](2) complex. However, in the structure of the triostin A-[d(GACGTC)](2) complex, two intermolecular hydrogen bonds between each of the Ala CO oxygens of the drug and the 2-amino protons of guanine are observed. These hydrogen bonds do not form in the CysMeTANDEM-DNA complex. Instead, CysMeTANDEM contains two intramolecular hydrogen bonds between the Ala CO atoms and the Val amide protons, making the Ala CO atoms unavailable to form two intermolecular hydrogen bonds. The role of these intermolecular hydrogen bonds in the CpG specificity of triostin A is discussed.