Experimental and Computational Hybrid Studies to Analyze Cellular Binding Partners of Cereblon

Abstract

Cereblon (CRBN), the substrate receptor of the cullin 4-RING E3 ligase complex, is the primary target protein for immunomodulatory drugs (IMiDs). Recent research has identified several CRBN binding proteins involved in metabolic pathways, yet more work is needed to explore new targets as well as the role of CRBN in the cell. In addition, more insight is also required into how mutations in CRBN affectas the first study in which CRBN is reported to interact directly with Hexokinase II. Finally, through quantum mechanics and molecular dynamic simulations, it was found that mutations in the Zn binding domain of CRBN cause changes on the protein binding interface with BKCa channels. This study combined several techniques in vitro and in silico in order to study how cellular binding partners interact with CRBN. The data provided here will help the design of new synthetic peptides for controlling the complex interactions and, more specifically, direct mechanisms in translational therapy in the future.