UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
J Am Chem Soc. 2013 Jan 30;135(4):1369-77. doi: 10.1021/ja308952y. Epub 2013 Jan 16.
High-resolution crystal structures of the DNA duplex sequence d(CGCGAATTCGCG)(2) complexed with three minor-groove ligands are reported. A highly conserved cluster of 11 linked water molecules has been found in the native and all 3 ligand-bound structures, positioned at the boundary of the A/T and G/C regions where the minor groove widens. This cluster appears to play a key structural role in stabilizing noncovalently binding small molecules in the AT region of the B-DNA minor groove. The cluster extends from the backbone phosphate groups along the mouth of the groove and links to DNA and ligands by a network of hydrogen bonds that help to maintain the ligands in position. This arrangement of water molecules is distinct from, but linked by, hydrogen bonding to the well-established spine of hydration, which is displaced by bound ligands. Features of the water cluster and observed differences in binding modes help to explain the measured binding affinities and thermodynamic characteristics of these ligands on binding to AT sites in DNA.
报道了与三个小沟配体结合的 d(CGCGAATTCGCG)(2)DNA 双链序列复合物的高分辨率晶体结构。在天然和所有 3 个配体结合结构中都发现了一个高度保守的、由 11 个相连水分子组成的簇，位于小沟变宽的 A/T 和 G/C 区域的边界处。该簇似乎在稳定非共价结合于 B-DNA 小沟 AT 区的小分子中发挥了关键的结构作用。该簇从骨架磷酸基团沿着沟的开口延伸，并通过氢键网络与 DNA 和配体相连，有助于将配体保持在适当的位置。这种水分子的排列方式与已确立的水合骨干结构不同，但通过氢键与之相连，而水合骨干结构被结合的配体所取代。水分子簇的特征和观察到的结合模式差异有助于解释这些配体在与 DNA 中 AT 位点结合时的测量结合亲和力和热力学特征。
