Iron homeostasis is crucial to bacterial survival. In Pseudomonas aeruginosa bacterioferritin (Pa-BfrB) stores excess iron as Fe3+, and releases it to the cytosol as Fe2+ under iron limiting conditions, thus contributing to bacterial iron homeostasis. Pa-BfrB is composed of 12 subunit dimers and each subunit dimer harbors a heme between, thus the 24-mer BfrB assembly contains 12 hemes and forms a hollow sphere where Fe3+ is stored. Iron release from Pa-BfrB requires interaction with a bacterioferritin-associated ferredoxin (Pa-Bfd), which is a 7.8 kDa protein harboring a [2Fe-2S] cluster, whose gene is located adjacent to the bfrb gene in a variety of pathogens. Yao, H et al. have demonstrated the interaction between Pa-BfrB and Pa-Bfd with the aid of biochemical and structural studies ('The Structure of the BfrB-Bfd Complex Reveals Protein-Protein Interactions Enabling Iron Release from Bacterioferritin', J Am Chem Soc. 2012,134 (32), pp 13470-13481). We are now exploring the possibility of discovering modulators of the BfrB-Bfd interaction as possible disruptors of bacterial iron homeostasis. As part of these efforts we are identifying the hotspot of the BfrB-Bfd interaction.  Key residues on BfrB that participate at the BfrB-Bfd interface have been mutated to Alanine. Binding affinity measurements and assays measuring the efficiency of iron release from mutant BfrB molecules indicate significantly weaker BfrB-Bfd interaction.  This information and its subsequent utilization in structure-based inhibitor design will be discussed.

Identifying the hot spot for the interaction between bacterioferritin (BfrB) and its associated ferredoxin (Bfd)

248th National Meeting (2014)

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