Modeling CRL4A ligase complex to predict target protein ubiquitination induced by CRBN-recruiting PROTACs

PROteolysis TArgeting Chimeras (PROTACs) are bifunctional small molecules that can simultaneously recruit target protein and E3 ligase to form a ternary complex (target protein / PROTAC / E3 ligase), leading to target protein ubiquitination and degradation via the Ubiquitin-Proteasome System (UPS). PROTACs have gained increasing attention in recent years due to certain advantages over traditional therapeutic modalities enabling targeting of previously "undruggable" proteins. To better understand the mechanism of PROTAC-induced Target Protein Degradation (TPD), several computational approaches have recently been developed to study and predict ternary complex formation. However, mounting evidence suggests that ubiquitination can also be a rate-limiting step in PROTAC induced TPD. Here, we propose a structure-based computational approach to predict target protein ubiquitination induced by CRBN-based PROTACs,