Clark G R, Squire C J, Gray E J, Leupin W, Neidle S
The CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
Nucleic Acids Res. 1996 Dec 15;24(24):4882-9. doi: 10.1093/nar/24.24.4882.
An analogue of the DNA binding compound Hoechst 33258, which has the para hydroxyl group altered to be at the meta position, together with the replacement of one benzimidazole group by pyridylimidazole, has been cocrystallized with the dodecanucleotide sequence d(CGCGAATTCGCG)2. The X-ray structure has been determined at 2.2 A resolution and refined to an R factor of 20.1%. The ligand binds in the minor groove at the sequence 5'-AATTC with the bulky piperazine group extending over the CxG base pair. This binding is stabilised by hydrogen bonding and numerous close van der Waals contacts to the surface of the groove walls. The meta-hydroxyl group was found in two distinct orientations, neither of which participates in direct hydrogen bonds to the exocyclic amino group of a guanine base. The conformation of the drug differs from that found previously in other X-ray structures of Hoechst 33258-DNA complexes. There is significant variation between the minor groove widths in the complexes of Hoechst 33258 and the meta-hydroxyl derivative as a result of these conformational differences. Reasons are discussed for the inability of this derivative to actively recognise guanine.
一种DNA结合化合物Hoechst 33258的类似物,其对位羟基被改变为间位,同时一个苯并咪唑基团被吡啶基咪唑取代,已与十二聚核苷酸序列d(CGCGAATTCGCG)2共结晶。X射线结构已在2.2埃分辨率下确定,并精修至R因子为20.1%。配体在5'-AATTC序列处结合于小沟,庞大的哌嗪基团延伸至CxG碱基对上方。这种结合通过氢键以及与沟壁表面众多紧密的范德华接触得以稳定。发现间位羟基处于两种不同取向,其中任何一种都不与鸟嘌呤碱基的环外氨基形成直接氢键。该药物的构象与先前在Hoechst 33258-DNA复合物的其他X射线结构中发现的构象不同。由于这些构象差异,Hoechst 33258与间位羟基衍生物的复合物中小沟宽度存在显著变化。讨论了该衍生物无法主动识别鸟嘌呤的原因。