9opj
cryoEM structure of IRAK4:KT-474:CRBN-DDB1 ternary complex
Structural highlights
DiseaseCRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry. FunctionCRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2] Publication Abstract from PubMedTargeted protein degradation has emerged as a promising drug modality, with potential applications across many immuno-inflammatory diseases. KT-474 is an orally bioavailable interleukin-1 receptor-associated kinase 4 (IRAK4) heterobifunctional degrader evaluated in clinical trials for atopic dermatitis and hidradenitis suppurativa. Here we present structural, biophysical, and computational characterization of an IRAK4:KT-474:CRBN/DDB1 complex. Cryo-EM structure of the complex reveals a unique and non-native protein-protein interaction (PPI) surface mediated by a network of polar and apolar contacts, including key hydrophobic engagements mediated by CRBN Phe150. This complex exhibits negative cooperativity, arising from an interplay between weakly favorable PPI and conformational flexibility of the degrader. Moreover, the structure provides insight into the selective degradation profile of KT-474. Our results offer important insights into the mechanism of action of KT-474 and highlight the value of cryo-EM structures in the optimization of protein degraders. Structural basis for selective and potent degradation of IRAK4 by KT-474.,Fei X, Ramanathan A, Daigle CA, Ford M, Campbell V, Zheng X, Sintchak M, Li H, Kamadurai H, Miller R, Kazmirski S, Huang X, Weiss MM, Mainolfi N, Zhu X Nat Commun. 2026 Jun 23. doi: 10.1038/s41467-026-74105-w. PMID:42336816[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
