9OPK

Crystal structure of IRAK4 with compound 1, an analog of KT-474 TBM

This is a non-PDB format compatible entry.

Summary for 9OPK

• Entry DOI: 10.2210/pdb9opk/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, (8R)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, heterobifunctional degrader, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 139406.54

Authors

Fei, X.,Ramanathan, A.,Diagle, C.,Ford, M.,Campbell, V.,Zheng, X.,Li, H.,Sintchak, M.,Kamadurai, H.,Miller, R.,Kazmirski, S.,Huang, X.,Weiss, M.,Manolfi, N.,Zhu, X. (deposition date: 2025-05-19, release date: 2026-07-29)

Primary citation

Fei, X.,Ramanathan, A.,Daigle, C.A.,Ford, M.,Campbell, V.,Zheng, X.,Sintchak, M.,Li, H.,Kamadurai, H.,Miller, R.,Kazmirski, S.,Huang, X.,Weiss, M.M.,Mainolfi, N.,Zhu, X.
Structural basis for selective and potent degradation of IRAK4 by KT-474.
Nat Commun, 2026

PubMed Abstract: 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.

PubMed: 42336816
DOI: 10.1038/s41467-026-74105-w

Experimental method

X-RAY DIFFRACTION (2.05 Å)