Eukaryotic translation initiation factor 3 subunit I – Cereblon – lenalidomide sequestration interface (eIF3i–CRBN–lenalidomide interface)

The Eukaryotic translation initiation factor 3 subunit I (eIF3i) – Cereblon (CRBN) – lenalidomide sequestration interface refers to a protein-protein interaction (PPI) complex induced by immunomodulatory drugs (IMiDs). Scientific literature [1, 2] indicates that while eIF3i is a known neo-substrate for the CRBN E3 ubiquitin ligase, it is specifically and potently recruited by the Cereblon E3 Ligase Modulator (CELMoD) CC-122 (Avadomide) rather than lenalidomide, which primarily targets IKZF1/3 and CK1alpha. In the presence of an appropriate molecular glue, CRBN undergoes a conformational change that allows it to bind eIF3i, leading to its sequestration from the eIF3 translation initiation complex or its subsequent polyubiquitination and proteasomal degradation [3, 4]. This disruption of the eIF3 complex inhibits protein synthesis, contributing to the anti-tumor activity of certain CRBN modulators in hematologic malignancies like multiple myeloma and diffuse large B-cell lymphoma [5]. The study of this interface is crucial for understanding the substrate specificity of different IMiD analogs and for the development of more selective therapeutic agents. Understanding the structural nuances of this interface is vital for developing next-generation CELMoDs with enhanced potency and reduced off-target effects. [1] Sievers et al. (2018) Science; [2] Hansen et al. (2021) J Med Chem; [3] Ito et al. (2010) Science; [4] Fischer et al. (2014) Nature; [5] Krönke et al. (2014) Science.

Other names

eIF3i-CRBN-CC-122 interfaceCereblon-eIF3i molecular glue complexCRBN-eIF3i-IMiD complex

Molecular glue-induced sequestration and proteasomal degradation of eIF3i via the CRL4-CRBN E3 ubiquitin ligase complex.