Mucormycosis is an invasive fungal infection with high mortality rate in immunocompromised individuals. Due to COVID-19 pandemic, the disease has resurfaced recently and lack of appropriate antifungals resulted in a poor outcome in patients. The iron uptake mechanism in Rhizopus delemar, the predominant causal agent, is crucial for its survival and pathogenesis in human host. The current study is first of its kind to focus on structural dynamics of high affinity iron permease (Ftr1), a virulence factor for Mucormycosis. Ftr1 is a transmembrane protein which is responsible for transport of Fe3+ ion from extracellular milieu to cytoplasm under iron starving conditions in Rhizopus. In this work, the three-dimensional modelling of Ftr1 was carried out. The Ftr1 possessed seven transmembrane helices with N- & C-termini in extracellular and intracellular regions respectively. Moreover, the present study delineates interaction of glutamic acid residues, found in the REGLE motif of fourth transmembrane helix with Fe3+. The molecular dynamics simulation study revealed that the glycine present in the motif destabilizes the helix thereby bringing E157 closer to positively charged ion. Understanding the interaction between Fe3+ ion and Ftr1 would be helpful in designing effective small molecule drugs against this novel therapeutic target for treating mucormycosis.
Keywords: Ftr1; Iron transport; Membrane protein simulation; Mucormycosis; Pore constriction; REGLE motif; Rhizopus delemar.
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