DNA bending by the HMG domain could explain preferential binding for AK6 and FF0 configurations.

<p>A cartoon based on the NMR-deduced structure of the HMG domain and basic tail (BT) of murine LEF-1 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004591#pgen.1004591-Love1" target="_blank">[80]</a> bending the HMG site. The HMG domain is composed of three alpha-helices (red barrels), the first of which binds the minor groove of the HMG site (shown in red), while the BT (red crescent) wraps around to make contact with the major groove. This binding induces a sharp bend in the DNA, most pronounced between positions T3 and T4 (CC<b><u>TT</u></b>TGATCTT). In TCF/Pan, which shares 92% identity with the HMG domain of LEF1, the BT is followed by a 10 residue linker, and then by the C-Clamp (blue oval), recently shown to chelate a zinc ion <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004591#pgen.1004591-Ravindranath1" target="_blank">[48]</a>. The C-clamp can bind to Helper sites (blue sequences) either upstream (AK) or downstream (FF) of the HMG site. We postulate that the linker places a constraint on the optimal spacing for the FF and AK orientation of 0 and 6 bp, respectively.