Structure of an MmyB-Like Regulator from C. aurantiacus, Member of a New Transcription Factor Family Linked to Antibiotic Metabolism in Actinomycetes

Actinomycetes are important bacterial sources of antibiotics and other secondary metabolites. Many antibiotic gene clusters are controlled by pathway-specific activators that act in response to growth conditions. Here we present the crystal structure of an MmyB-like transcription regulator MltR (PDB code 3pxp) (Caur_2278) from Chloroflexus aurantiacus, in complex with a fatty acid (myristic acid). MltR is a distant homolog of the methylenomycin activator MmyB and consists of an Xre-type N-terminal DNA-binding domain and a C-terminal ligand-binding module that is related to the Per-Arnt-Sim (PAS) domain. This structure has enabled identification of a new family of bacterial transcription factors that are distributed predominantly in actinomycetes. Bioinformatics analysis of MltR and other characterized family members suggest that they are likely associated with antibiotic and fatty acid metabolism in actinomycetes. Streptomyces coelicolor SCO4944 is a candidate as an ancestral member of the family. Its ortholog in S. griseus, SGR_6891, is induced by A-factor, a γ-butyrolactone that controls antibiotic production and development, and is adjacent to the A-factor synthase gen, afsA. The location of mltR/mmyB homologs, in particular those adjacent to less well-studied antibiotic-related genes, makes them interesting genetic markers for identifying new antibiotic genes. A model for signal-triggered DNA-binding by MltR is proposed.