1- Crystal of the QacR homodimer bound to DQ120
QacR is an homodimer. Each QacR monomer is formed by 9 alpha-helices.
Place the pointer in the figure over the helix of the blue monomer that you wish to identify.
The DNA-binding domain is structurally similar to that of TetR.
The regulatory domain of QacR involved in multidrug recognition and dimerization is composed by six helices from alpha 4 to alpha 9 in contrast to TetR in which seven helices constitute this domain.
QacR regulatory domain does not display sequence-similarity to TetR but it has been detected a structural similarity at the level of the dimerization interface that also contains a "double X motif". This motif is drawn by the helices alpha 8 and alpha 9 and their symmetric antiparallel alpha 8' and alpha 9' in QacR and by alpha 8 and alpha 10 and their symmetric alpha 8' and alpha 10' in TetR homodimer.
As in TetR the induction mechanism begins with a conformational change in the regulatory domain triggered by drug binding. This movement is transmitted to the two DNA-binding domains that increase their separation disrupting the binding to DNA. Binding of the drug triggers a coil-to-helix transition in alpha 5 that relocates alpha 6 and provokes the pendulum motion of alpha 4 as in TetR.
In QacR homodimer the drug-induced conformational changes are asymmetric. Although there are two pockets in each QacR homodimer there are only one molecule of drug per homodimer. This is the cause of the asymmetric induction process in which the drug-bound monomer suffers a major structural change that the drug-free monomer.
The QacR binding-pocket is capable of accommodating an ample set of cationic lipophilic drugs. The pocket is large and multifaceted and has a volume of 1100 A3 with several binding sites that overlap. In the QacR drug-binding pocket there are negative residues to neutralize cations and aromatic and polar residues and water molecules accommodate multiple drugs.
QacR is a homodimer similar to TetR with two DNA-binding domains very similar to TetR that interact with DNA major groove. However, two QacR homodimers bind the operator site. In the figure we have named A proximal and A distal the two monomers that form the dimer A, and B proximal and B distal those of dimer B, depending on their position with respect to the centre of symmetry of the palindromic operator.
The figures were prepared with WebLab Viewer (Molecular Simulations Inc.)