The structural basis of acyl coenzyme A-dependent regulation of the transcription factor FadR

FadR is an acyl-Coh-responsive transcription factor, regulating fatty acid biosynthetic and degradation genes in Escherichia coli, The ape-protein bin ds DNA as a homodimer, an interaction that is disrupted by binding of acyl- CoA, The recently described structure of apo-FadR shows a DNA binding domai n coupled to an acyl-CoA binding domain with a novel fold, but does not exp lain how binding of the acyl-CoA effector molecule > 30 Angstrom away from the DNA binding site affects transcriptional regulation. Here, we describe the structures of the FadR-operator and FadR-myristoyl-CoA binary complexes . The FadR-DNA complex reveals a novel winged helix-turn-helix protein-DNA interaction, involving sequence-specific contacts from the wing to the mino r groove. Binding of acyl-CoA results in dramatic conformational changes th roughout the protein, with backbone shifts up to 4.5 Angstrom, The net effe ct is a rearrangement of the DNA binding domains in the dimer, resulting in a change of 7.2 Angstrom in separation of the DNA recognition helices and the loss of DNA binding, revealing the molecular basis of acyl-CoA-responsi ve regulation.