From Structure to Specificity: Investigating the Molecular Framework of RNF E3 Ligases and Substrate Interactions

Author(s): Valentyna Tararina, Oleksandra Makhankova, Oleksandr Zholos

Affiliation(s): Taras Shevchenka National University of Kyiv, Ukraine



In recent years, monovalent degraders have emerged as a new strategy in drug development, offering the potential to selectively eliminate disease-causing proteins. However, most of the known molecular glues were discovered by chance and there is currently no specific approach to the development of molecular degraders. By shedding light on the functioning of E3 ligases, we offer valuable information that can be further used to design targeted protein degradation. Our study provides an enhanced understanding of the sequence and structural elements in the RNF family and represents a new bioinformatic tool specifically designed for this purpose. Using this tool, we have identified key amino acid sequences that underlie substrate recognition in RNF E3 ligases, allowing us to compile an expanded list of potential substrates within the RNF family spanning diverse cellular processes. In summary, our study contributes to the growing body of knowledge about protein degradation-based therapies. By dissecting the structural variation in the RNF E3 family of ligases and their interactions with substrates, we lay the groundwork for future research efforts aimed at pinpointing proteins for degradation, thus paving the way for the development of personalized medicine and the treatment of a wide range of diseases.