Investigating the Mechanism of Iron Dependent Repressor (IDER) Activation and DNA Binding

Abstract

Metalloproteins form a major class of enzymes in the living system and are involved in critical biological functions such as catalysis, redox reactions and as “switches” in signal transductions. Iron dependent repressor (IdeR) is a metal-sensing transcription factor that regulates free iron concentration in Mycobacterium tuberculosis. IdeR is also known to promote bacterial virulence, making it an important protein for therapeutics.In this study, we have employed molecular dynamic simulations on different binding states of IdeR in the presence and absence of iron to study its influence on protein function. Structures were investigated using hydrogen bonds and protein structure networks and displayed significant variation between the metallated and the non-metallated systems. Briefly, we could establish the role of iron in stabilizing the monomeric unit of IdeR which in turn promotes protein dimerization. Two major monomer conformations, “open” and “closed” were identified and their geometrical parameters were also quantified. Perhaps, the most striking results are obtained from the simulations of the IdeR-DNA complex in the absence of metals, where the protein subunits are seen to dissociate away from the DNA quite rapidly. Such drastic changes in the IdeR-DNA interactions not only provide molecular insights about the role of iron, but also about the mechanism of DNA binding and unbinding. Based on the ensemble structure analysis, we suggest the role of iron as a possible allosteric effector that enhances the IdeR-DNA interactions.Our simulation results enable us to understand the sequence of events that govern IdeR-DNA binding in the presence of iron.