A dimeric DNA interface stabilized by stacked A•(G•G•G•G)•A hexads and coordinated monovalent cations
A dimeric DNA interface stabilized by stacked A•(G•G•G•G)•A hexads and coordinated monovalent cations
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DOI：
10.1006/jmbi.2000.3524
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发表时间：
2000-03-31
影响因子：
5.6
通讯作者：
Patel, DJ
中科院分区：
文献类型：
--
作者：
Kettani, A;Gorin, A;Patel, DJ
我们报告一名a。(g.g.g.g。G)通过剪切的G.A错配形成，六边形配对比对包括识别在g.g.g.g.g四分体中暴露的相对鸟嘌呤的小凹槽。在150 mM Na+（或K+）阳离子溶液中，发现了d（G-G-A-G-G-A-G）序列，其中四个对称相关的链排列成一个新的二聚基序。二聚体“六边形”基序的每一个对称的一半由两条链组成，并包含一个a （G.G.G.）的堆叠阵列G)一个六分体，一个G.G.G.G四分体，一个A.A不匹配。六边形基序中的每条链包含两个连续的转弯，它们一起定义了一个s形的双链反转折叠，它连接了沿着四重体相邻边缘平行排列的两个G-G步骤。我们的研究还为d（G-G- a -G-G- a -N）序列（N = T和G）建立了一种新的结构转变，从通过10 mM Na+溶液中的交叉链堆叠和错配形成稳定的“箭头”基序（先前报道），到通过广泛的亚基间对称相关的a （G-G- G）堆叠稳定的二聚体六体基序。在150mm的Na+溶液中。通过结合布朗动力学和无约束分子动力学计算，探索了箭头和六元基序内潜在的单价阳离子结合位点。我们无法在低盐箭头基序中确定稳定的单价阳离子结合位点。相比之下，在中盐二聚体六元基序中发现了5个电负性口袋。其中三个涉及夹在四聚体平面之间的阳离子结合位点，另外两个涉及跨越与相邻堆叠a （G.G.G.G）相关的未占用凹槽的水介导的阳离子结合位点。六个一组。我们对a （g.g.g.g.g）的演示。六元体的形成为设计富含腺嘌呤的g -四元体相互作用低聚物提供了机会，这些低聚物可能潜在地靶向堆叠的g.g.g.g.g四元体的碱基边缘。这种方法可以补充目前设计凹槽结合和嵌入配体的努力，这些配体旨在阻止端粒酶的活性。(C) 2000年学术出版社。
We report on the identification of an A.(G.G.G.G) A hexad pairing alignment which involves recognition of the exposed minor groove of opposing guanines within a G.G.G.G tetrad through sheared G.A mismatch formation. This unexpected hexad pairing alignment was identified for the d(G-G-A-G-G-A-G) sequence in 150 mM Na+ (or K+) cation solution where four symmetry-related strands align into a novel dimeric motif. Each symmetric half of the dimeric "hexad" motif is composed of two strands and contains a stacked array of an A.(G.G.G.G) A hexad, a G.G.G.G tetrad, and an A.A mismatch. Each strand in the hexad motif contains two successive turns, that together define an S-shaped double chain reversal fold, which connects the two G-G steps aligned parallel to each other along adjacent edges of the quadruplex. Our studies also establish a novel structural transition for the d(G-G-A-G-G-A-N) sequence, N = T and G, from an "arrowhead" motif stabilized through cross-strand stacking and mismatch formation in 10 mM Na+ solution (reported previously), to a dimeric hexad motif stabilized by extensive inter-subunit stacking of symmetry-related A.(G G-G G).A hexads in 150 mM Na+ solution. Potential monovalent cation binding sites within the arrowhead and hexad motifs have been probed by a combination of Brownian dynamics and unconstrained molecular dynamics calculations. We could not identify stable monovalent cation-binding sites in the low salt arrowhead motif. BY contrast, five electronegative pockets were identified in the moderate salt dimeric hexad motif. Three of these are involved in cation binding sites sandwiched between G.G.G.G tetrad planes and two others, are involved in water-mediated cation binding sites spanning the unoccupied grooves associated with the adjacent stacked A.(G.G.G.G).A hexads. Our demonstration of A.(G.G.G.G).A hexad formation opens opportunities for the design of adenine-rich G-quadruplex-interacting oligomers that could potentially target base edges of stacked G.G.G.G tetrads. Such an approach could complement current efforts to design groove-binding and intercalating ligands that target G-quadruplexes in attempts designed to block the activity of the enzyme telomerase. (C) 2000 Academic Press.