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bioRxiv · 10.1101/2024.04.27.591468

Probing the Molecular Interactions of A22 with Prokaryotic Actin MreB and Eukaryotic Actin: A Computational and Experimental Study

Kumar, A.·Kukal, S.·Marepalli, A.·Kumar, S.·Govindarajan, S.·Pramanik, D.
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Abstract

Actin is a major cytoskeletal system that mediates the intricate organization of macromolecules within cells. The bacterial cytoskeletal protein MreB is a prokaryotic actin-like protein governing cell shape and intracellular organization in many rod-shaped bacteria including pathogens. MreB stands as a target for antibiotic development, and compounds like A22 and its analogue, MP265, are identified as potent inhibitors of MreB. The bacterial actin MreB shares structural homology with eukaryotic actin, despite lacking sequence similarity. It is currently not clear whether small molecules that inhibit MreB can act on the eukaryotic actin due to their structural similarity. In this study, we investigate the molecular interactions between A22 and both MreB and eukaryotic actin through molecular dynamics approach. Employing MD simulations and free energy calculations with an all-atom model, we unveil robust A22-MreB interaction and substantial binding affinity with eukaryotic actin. Experimental assays reveal A22s toxicity to eukaryotic cells, including yeast and human glioblastoma cells. Microscopy analysis demonstrates profound effects of A22 on actin organization in human glioblastoma cells. Overall, this integrative computational and experimental study advances our understanding of A22s mode of action and highlights its potential as a versatile tool for probing actin dynamics and as a candidate for therapeutic intervention in pathological conditions like cancer.

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Kumar, A., Kukal, S., Marepalli, A., Kumar, S., Govindarajan, S., Pramanik, D.. 2024-04-29. Probing the Molecular Interactions of A22 with Prokaryotic Actin MreB and Eukaryotic Actin: A Computational and Experimental Study. https://doi.org/10.1101/2024.04.27.591468

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