How NF-κB can be attracted by its cognate DNA

NF-kappa B is involved in the transcriptional regulation of a large number of genes, in particular those of human immunodeficiency virus (HIV). Recently, we used NMR spectroscopy and molecular modelling to study the solution structure of a native duplex related to the HIV-1 kappa B site, together with a mutated duplex for which a three base-pair change abolishes NF-kappa B binding. The native duplex shows unusual dynamics of the four steps surrounding the kappa B site. Here, we explore the intrinsic properties of the NMR-refined structures of both duplexes in order to understand why the native sequence is recognised by NF-kappa B among other DNA sequences. We establish that only the native kappa B Site can adopt a conformation where its structure (curvature and base displacement), the accessibility and the electrostatic potentials of key atoms become very favourable for binding the large loops of NF-kappa B, in contrast to the mutated duplex. Finally, we show that the neutralisation of phosphate groups contacted by NF-kappa B favours a more canonical DNA structure. These findings lead to a new hypothesis for specific recognition through the phosphodiester backbone dynamics of the sequences flanking a binding site. Such unusual behaviour confers upon the overall duplex properties that can be used by NF-kappa B to select its binding site. Thus, the selectivity determinants for NF-kappa B binding appear to depend on deformability of an "extended" consensus sequence. (C) 1999 Academic Press.