Abstact

Clostridioides difficile is a pathogenic bacterium responsible for illnesses ranging from diarrhea to life-threatening colitis and has emerged as a significant public health concern due to its resistance to antibiotics. During its infection, intestinal bleeding causes lysis of the red blood cells releasing heme, a toxic oxidant for the bacterium. To counteract, HsmR of the MarR family transcriptional regulator senses the heme and induces the expression of HsmA to sequester the heme. The structure of HsmR in complex with its cognate pseudo-palindromic DNA illustrates that the lysine and arginine of the winged helix-turn-helix motif undergo conformational changes to accommodate the DNA, and to interact with specific DNA bases. However, conservation of these residues in half of 14 or so C. difficile MarRs within its genome raises a question on how specificity between MarR and DNA is achieved. Comparisons of various C. difficile MarR structures suggest that they probably have acquired DNA selectivity by the slightly different dimeric mode mediated by mutual interaction between the first helices of each HsmR subunit. The unique HsmR dimer mode allows symmetric recognition toward its own cognate DNA, and heme binding would happen in concert with reorientation of these helices in turn affecting DNA binding.