Developing a comprehensive solution aimed to disrupt LARS1/RagD protein-protein interaction

Abstract

Aminoacyl-tRNA synthetases are crucial enzymes involved in protein synthesis and various cellular physiological reactions. Aside from their standard role in linking amino acids to the corresponding tRNAs, they also impact protein homeostasis by controlling the level of soluble amino acids within the cell. For instance, leucyl-tRNA synthetase (LARS1) acts as a leucine sensor for the mammalian target of rapamycin complex 1 (mTORC1), and may also function as a probable GTPase-activating protein (GAP) for the RagD subunit of the heteromeric activator of mTORC1. In turn, mTORC1 regulates cellular processes, such as protein synthesis, autophagy, and cell growth, and is implicated in various human diseases including cancer, obesity, diabetes, and neurodegeneration. Hence, inhibitors of mTORC1 or a deregulated mTORC1 pathway may offer potential cancer therapies. In this study, we investigated the structural requirements for preventing the sensing and signal transmission from LARS to mTORC1. Building upon recent studies on mTORC1 regulation activation by leucine, we lay the foundation for the development of chemotherapeutic agents against mTORC1 that can overcome resistance to rapamycin. Using a combination of in-silico approaches to develop and validate an alternative interaction model, discussing its benefits and advancements. Finally, we identified a set of compounds ready for testing to prevent LARS1/RagD protein-protein interactions. We establish a basis for creating chemotherapeutic drugs targeting mTORC1, which can conquer resistance to rapamycin. We utilize in-silico methods to generate and confirm an alternative interaction model, outlining its advantages and improvements, and pinpoint a group of novel substances that can prevent LARS1/RagD interactions.

Communicated by Ramaswamy H. Sarma

Keywords:

• AlphaFold
• leucyl-tRNA synthetase
• LARS1
• mTORC1 signaling
• rapamycin
• resistance

Acknowledgments

Virtual screening software and screening libraries were provided by Enamine Ltd. The acknowledgment is also given to Dr. Somayeh Pirhadi at the Biochemistry and Molecular Biotechnology department of the University of Massachusetts Chan Medical School for the helpful comments on applying MD simulation methods. Likewise, authors are grateful to Mr. Vladimir Rayevsky for the valuable assistance with graph visualizations of the manuscript.

Disclosure statement

The authors declare no conflict of interest, financial or otherwise.

Data availability statement

Research data are not shared.

Additional information

Funding

The work was supported by the National Research Foundation of Ukraine (https://nrfu.org.ua/) under the project ‘The nonproteinogenic leucine analogues in leucine-induced mTORC1 signaling in human cells’, State Registration № 0221U101266, and using the capacities of the Grid Clusters of the Institute of Molecular Biology and Genetics and Institute of Food Biotechnology and Genomics of the National Academy of Sciences of Ukraine.