Ribosome: assembly, structure-function, dynamics & drug-design
Ribosomes are the protein synthesis machineries of the cell. Protein synthesis is a fundamental cellular process that consumes nearly half of the cell's resources, and ~40% of the known antibiotics target it. Our research focuses on protein synthesis and ribosome in pathogenic microbes, mainly Mycobacterium tuberculosis (Mtb), which causes the deadliest disease, tuberculosis, and Entamoeba histolytica (Eth), which causes amoebiasis. synthesis machinery, the ribosome. The research goal is to find out the unique features of protein synthesis in these pathogens and exploit them for novel inhibitor design. In Mtb, the research focuses on understanding how the pathogen survives for decades in the hostile environment of the host macrophage in a dormant state. It is also believed that nearly one-third of the world’s population possesses the dormant Mtb, which serves as a huge reservoir for tuberculosis infection. We have reported a cryo-EM structure M. smegmatis ribosome, in complex with RafH protein at 2.8 Å resolution in Nature Communication (2024). RafH is a hypoxia stress-induced ribosome hibernation promotion factor. In the near future, we would like to understand mycobacterial survival under other stresses such as nutritional starvation, multiple stresses, etc. In Eth, our laboratory has reported the cryo- EM structures of its ribosome at 2.8 – 3.2 Å resolution in Nature Communications (2025). This study reveals several unique features such as rRNA triple helix and helical assembly of Eth ribosome. In the future, we would like to determine its functional complexes and understand the structural basis of helical assembly. Ribosomes must assemble accurately to perform error-free translation. Defects in ribosome assembly are associated with diseases such as cancer, age-related degenerative diseases, and aging. We aim to understand the ribosome assembly process by depleting the ribosome assembly factors, such as GTPase, and trapping ribosomes in an assembly intermediate stage. Ultimately, determining the cryo-EM structure of assembly intermediates.