Crystal structure of FadR, a fatty acid-responsive transcription factor with a novel acyl coenzyme A-binding fold

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Abstract
FadR is a dimeric acyl coenzyme A (acyl CoA)‐binding protein and transcription factor that regulates the expression of genes encoding fatty acid biosynthetic and degrading enzymes in Escherichia coli. Here, the 2.0 Å crystal structure of full‐length FadR is described, determined using multi‐wavelength anomalous dispersion. The structure reveals a dimer and a two‐domain fold, with DNA‐binding and acyl‐CoA‐binding sites located in an N‐terminal and C‐terminal domain, respectively. The N‐terminal domain contains a winged helix–turn–helix prokaryotic DNA‐binding fold. Comparison with known structures and analysis of mutagenesis data delineated the site of interaction with DNA. The C‐terminal domain has a novel fold, consisting of a seven‐helical bundle with a crossover topology. Careful analysis of the structure, together with mutational and biophysical data, revealed a putative hydrophobic acyl‐CoA‐binding site, buried in the core of the seven‐helical bundle. This structure aids in understanding FadR function at a molecular level, provides the first structural scaffold for the large GntR family of transcription factors, which are keys in the control of metabolism in bacterial pathogens, and could thus be a possible target for novel chemotherapeutic agents.