School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld 4072, Australia
Haemophilus influenzae is a major cause of lower respiratory tract diseases. This and other pathogenic bacteria must cope with a range of electrophiles generated in the host or by endogenous metabolism. Formaldehyde is one such compound that can irreversibly damage proteins and DNA through alkylation and cross-linking and interfere with redox homeostasis. HiNmlR is the transcription factor that controls the detoxification of formaldehyde in H. influenzae. NmlR belongs to the MerR family of transcription factors, but lacks a specific sensor region and does not bind metal ions. We demonstrate that HiNmlR is a thiol-dependent transcription factor that modulates H. influenzae response to formaldehyde, with two cysteine residues (Cys54 and Cys71) identified to be important for its response against a formaldehyde challenge. We obtained crystal structures of HiNmlR in both the DNA-free and two DNA-bound forms, which suggest that HiNmlR enhances target gene transcription by twisting of operator DNA sequences in a two-gene operon containing overlapping promoters. Our work provides the first structural insights into the mechanism of action of MerR regulators that lack sensor regions (Counago et al (2016) Nucleic Acids Res, in press).