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TitleStructural basis for selective and potent degradation of IRAK4 by KT-474.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJun 23, 2026
AuthorsXue Fei / Anand Ramanathan / Caroline A Daigle / Melissa Ford / Veronica Campbell / Xiaozhang Zheng / Mike Sintchak / Haoran Li / Hari Kamadurai / Richard Miller / Steven Kazmirski / Xin Huang / Matthew M Weiss / Nello Mainolfi / Xiao Zhu /
PubMed AbstractTargeted 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- ...Targeted 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.
External linksNat Commun / PubMed:42336816
MethodsEM (single particle) / X-ray diffraction
Resolution2.05 - 3.2 Å
Structure data

70719

9opj

EMDB-70719, PDB-9opj:
cryoEM structure of IRAK4:KT-474:CRBN-DDB1 ternary complex
Method: EM (single particle) / Resolution: 3.2 Å

PDB-9opk:
Crystal structure of IRAK4 with compound 1, an analog of KT-474 TBM
Method: X-RAY DIFFRACTION / Resolution: 2.05 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1cdc:
CD2, N-TERMINAL DOMAIN (1-99), TRUNCATED FORM

PDB-1cdd:
STRUCTURES OF APO AND COMPLEXED ESCHERICHIA COLI GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-GOL:
GLYCEROL

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsTransferase/DNA-Binding Protein / Kinase / E3 ligase / IRAK4 / CRBN / DDB1 / heterobifunctional degrader / Transferase-DNA-Binding Protein complex / TRANSFERASE / inhibitor

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