Abstract
Metalloproteins form a major class of enzymes in the living system that are involved in crucial 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 target in the field of therapeutics. Mechanistic details of how iron ions modulate IdeR such that it dimerizes and binds to DNA is not understood clearly. In this study, we have performed molecular dynamic simulations and integrated it with protein structure networks to study the influence of iron on IdeR structure and function. A significant structural variation between the metallated and the non-metallated system is observed. Our simulations clearly indicate the importance of iron in stabilizing its monomeric subunit, which in turn promotes dimerization. However, the most striking results are obtained from the simulations of IdeR-DNA complex in the absence of metals, where at the end of 100ns simulations, the protein subunits are seen to rapidly dissociate away from the DNA, thereby forming an excellent resource to investigate the mechanism of DNA binding. We have also investigated the role of iron as an allosteric regulator of IdeR that positively induces IdeR-DNA complex formation. Based on this study, a mechanistic model of IdeR activation and DNA binding has been proposed.
Highlights
Tuberculosis (TB) remains the largest killer amongst infectious diseases globally and is caused by the pathogen Mycobacterium tuberculosis (M.tb)
Macromolecules possess an inherent dynamicity that enables them to perform a myriad of biological functions
We have investigated the influence of iron on the structure and function of Iron dependent repressor (IdeR), which in turn triggers a cascade of events responsible for maintaining iron concentrations in the bacterial cell
Summary
Tuberculosis (TB) remains the largest killer amongst infectious diseases globally and is caused by the pathogen Mycobacterium tuberculosis (M.tb). Extraction of iron from the host cell is considered to be one of the crucial factors, required for M.tb virulence [4]. A stiff competition exist between the host and the pathogen for the extraction of iron, which in turn determines the outcome of infection [6,7]. Excess of free iron can be toxic for the organisms as free iron can undergo Fenton reaction and produce harmful oxygen radicals. This necessitates the need for fine regulation of iron concentration in both the systems. IdeR is a well-characterized protein, with crystal structures available at various levels of accuracy and resolution [9,10]
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