Mechanism of Lac repressor switch-off: orientation of the Lac repressor DNA-binding domain is reversed upon inducer binding.

Lac repressor's DNA-binding domains contain helix-turn-helix motif which, though similar to those of phage lambda Cro protein, are oriented differently with respect to DNA: in the specific complexes with Lac operator, N termini of the repressor's subunits are facing inwards. We demonstrate that, in the presence of an inducer, the repressor's N termini cross-link to the operator's outermost nucleotides. We suggest that the inducer fixes the repressor's DNA-binding domains in the Cro-type configuration and thus garbles its recognition surface. Since the Cro-type configuration is perfectly suitable for binding the DNA, this also explains how the switched-off repressor retains its non-specific DNA-binding.