Data generated from the simulation of the structures of the CRL4 E3 ligase from Homo sapiens and their homolgs of Trypanosoma cruzi, Trypanosoma brucei and Leishmania major using MultimerMapper

Abstract

In recent years, compounds known as Proteolysis Targeted Chimeras (PROTACs) have revitalized the field of bioactive molecule design. These compounds promote proteolysis of therapeutic targets by recruiting them to ubiquitin ligases. One of the most widely used classes of compounds for PROTAC synthesis are immunomodulatory imides (IMiDs), such as thalidomide (TLD), which interact with the E3 ligase CRL4CRBN through the CULT domain of the cereblon protein (CRBN). This domain has been identified in proteins from various phylogenetic groups, including trypanosomatids, leading to the hypothesis that IMiD-derived PROTACs could be active in these organisms. In this study, we conducted an exhaustive search for possible components of this CRL4 E3 ligase in trypanosomatids, based on the corresponding sequences. Using Alpha-Fold and MultimerMapper, we performed an in silico structural analysis of the potential components of a CRL4CRBN-type E3 ligase complex, revealing that the trypanosomal CULT domain protein is not part of this complex. This study indicates that while PROTACs hold promise for human therapeutics, the rationale for thalidomide-based PROTACs in trypanosomatid research needs to be re-evaluated.