Mechanism of inhibition of DNA gyrase by quinolone antibacterials: specificity and cooperativity of drug binding to DNA.
Mechanism of inhibition of DNA gyrase by quinolone antibacterials: specificity and cooperativity of drug binding to DNA.
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DOI：
10.1021/bi00435a038
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发表时间：
1989-05
期刊：
影响因子：
2.9
通讯作者：
Linus L. Shen;J. Baranowski;A. Pernet
中科院分区：
文献类型：
--
作者：
Linus L. Shen;J. Baranowski;A. Pernet
尽管奈利地酸和诺氟沙星等喹诺酮类抗菌药物的功能靶点已被确定为DNA旋转酶，但药物的直接结合部位是DNA分子[Shen.L.L.&Pernet，A.G.(1985)Proc]。娜塔莉。阿卡德。SCI。美国第82号，307-311号]。利用多种不同结构和不同碱基组成的DNA物种，进一步研究了喹诺酮类药物与DNA的结合专一性和协同性。结果表明，药物结合的特异性在很大程度上由DNA结构控制和决定。当DNA链配对时，该药物结合较弱，没有表现出碱基偏好。当链分离时，药物以更大的亲和力结合，因此出现结合偏好：它与聚(G)和聚(DG)结合得更好，而不是它们的对应物，包括聚(Di)。结果表明，该药物通过氢键结合到未配对的碱基上，而不是通过与DNA碱基的环堆积。与松弛的双链DNA的弱结合和与单链DNA的较强结合都是非特异性的，因为它们不表现出结合的饱和性和协同性。具体的结合类型，最初在我们之前的出版物中展示了与超螺旋dna，最近与线性dna和dna旋转酶之间形成的复合体[沈，L.，Kohlbrenner，W.E.，Weigl，D.，&Baranowski，J.()J.Biol。化学。(在媒体中)]，发生在药物的超螺旋抑制浓度附近。如本文所示，这种类型的结合饱和度曲线具有很强的协同性(希尔常数大于4)。
Although the functional target of quinolone antibacterials such as nalidixic acid and norfloxacin has been identified as the enzyme DNA gyrase, the direct binding site of the drug is the DNA molecule [Shen, L. L., & Pernet, A. G. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 307-311]. As described in this paper, binding specificity and cooperativity of quinolones to DNA were further investigated with the use of a variety of DNA species of different structures and different base compositions. Results show that the drug binding specificity is controlled and determined largely by the DNA structure. The drug binds weakly and demonstrates no base preference when DNA strands are paired. The drug binds with much greater affinity when the strands are separated, and consequently, binding preference emerges: it binds better to poly(G) and poly(dG) over their counterparts including poly(dI). The results suggest that the drug binds to unpaired bases via hydrogen bonding and not via ring stacking with DNA bases. The weak binding to relaxed double-stranded DNA and the stronger binding to single-stranded DNA are both nonspecific as they do not demonstrate binding saturation and cooperativity. The specific type of binding, initially demonstrated in our previous publication with the supercoiled DNA and more recently with complex formed between linear DNA and DNA gyrase [Shen, L. L., Kohlbrenner, W. E., Weigl, D., & Baranowski, J. (1989) J. Biol. Chem. (in press)], occurs near the drug's supercoiling inhibition concentration. As shown in this paper, binding saturation curves of this type are highly cooperative (with Hill constant greater than 4).(ABSTRACT TRUNCATED AT 250 WORDS)