Roy Choudhury Ahana, Murali Ayaluru
Department of Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India.
J Mol Graph Model. 2025 Jan;134:108907. doi: 10.1016/j.jmgm.2024.108907. Epub 2024 Nov 13.
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.
毛霉病是一种侵袭性真菌感染，在免疫功能低下的个体中死亡率很高。由于新冠疫情，这种疾病最近再次出现，且缺乏合适的抗真菌药物导致患者预后不良。主要病原体德氏根霉的铁摄取机制对其在人类宿主中的生存和发病机制至关重要。当前的这项研究首次聚焦于高亲和力铁通透酶（Ftr1）的结构动力学，Ftr1是毛霉病的一种毒力因子。Ftr1是一种跨膜蛋白，在根霉铁饥饿条件下负责将Fe3+离子从细胞外环境转运到细胞质中。在这项工作中，对Ftr1进行了三维建模。Ftr1拥有七个跨膜螺旋，其N端和C端分别位于细胞外和细胞内区域。此外，本研究还描述了在第四个跨膜螺旋的REGLE基序中发现的谷氨酸残基与Fe3+的相互作用。分子动力学模拟研究表明，该基序中存在的甘氨酸使螺旋不稳定，从而使E157更靠近带正电荷的离子。了解Fe3+离子与Ftr1之间的相互作用将有助于设计针对这种新型治疗靶点的有效小分子药物，以治疗毛霉病。
