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- PDB-9opj: cryoEM structure of IRAK4:KT-474:CRBN-DDB1 ternary complex -

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Basic information

Entry
Database: PDB / ID: 9opj
TitlecryoEM structure of IRAK4:KT-474:CRBN-DDB1 ternary complex
Components
  • DNA damage-binding protein 1
  • Interleukin-1 receptor-associated kinase 4
  • Protein cereblon
KeywordsTransferase/DNA-Binding Protein / Kinase / E3 ligase / IRAK4 / CRBN / DDB1 / heterobifunctional degrader / Transferase-DNA-Binding Protein complex
Function / homology
Function and homology information


IRAK4 deficiency (TLR5) / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / interleukin-33-mediated signaling pathway / regulation of MAP kinase activity / neutrophil migration / NLRP3 inflammasome complex assembly / negative regulation of monoatomic ion transmembrane transport ...IRAK4 deficiency (TLR5) / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / interleukin-33-mediated signaling pathway / regulation of MAP kinase activity / neutrophil migration / NLRP3 inflammasome complex assembly / negative regulation of monoatomic ion transmembrane transport / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / positive regulation by virus of viral protein levels in host cell / interleukin-1-mediated signaling pathway / spindle assembly involved in female meiosis / toll-like receptor 4 signaling pathway / epigenetic programming in the zygotic pronuclei / IRAK4 deficiency (TLR2/4) / serine/threonine protein kinase complex / extrinsic component of plasma membrane / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / MyD88-dependent toll-like receptor signaling pathway / UV-damage excision repair / toll-like receptor signaling pathway / biological process involved in interaction with symbiont / regulation of mitotic cytokinesis / regulation of mitotic cell cycle phase transition / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding / regulation of cell cycle phase transition / locomotory exploration behavior / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / limb development / viral release from host cell / lipopolysaccharide-mediated signaling pathway / JNK cascade / cullin family protein binding / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / regulation of DNA-templated DNA replication initiation / positive regulation of viral genome replication / positive regulation of gluconeogenesis / canonical NF-kappaB signal transduction / positive regulation of smooth muscle cell proliferation / rhythmic process / regulation of embryonic development / replication fork processing / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / proteasomal protein catabolic process / epigenetic regulation of gene expression / positive regulation of protein-containing complex assembly / nucleotide-excision repair / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / kinase activity / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / cell population proliferation / cytokine-mediated signaling pathway / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / Interleukin-1 signaling / cellular response to UV / positive regulation of protein catabolic process / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / PIP3 activates AKT signaling / regulation of cell population proliferation / site of double-strand break / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Neddylation / spermatogenesis / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / transmembrane transporter binding / innate immune response / positive regulation of canonical NF-kappaB signal transduction / chromosome, telomeric region / non-specific serine/threonine protein kinase / protein-macromolecule adaptor activity / intracellular signal transduction / protein ubiquitination / endosome membrane / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response
Similarity search - Function
Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily ...Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / : / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / PUA-like superfamily / Death-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Serine/Threonine protein kinases, catalytic domain / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / DNA damage-binding protein 1 / Protein cereblon / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFei, X. / Ramanathan, A. / Diagle, C. / Ford, M. / Campbell, V. / Zheng, X. / Li, H. / Sintchak, M. / Kamadurai, H. / Miller, R. ...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.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for selective and potent degradation of IRAK4 by KT-474.
Authors: Xue Fei / Anand Ramanathan / Caroline A Daigle / Melissa Ford / Veronica Campbell / Xiaozhang Zheng / Mike Sintchak / Haoran Li / Hari Kamadurai / Richard Miller / Steven Kazmirski / Xin ...Authors: Xue 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 /
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- ...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.
History
DepositionMay 19, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
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Revision 1.1Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
Z: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,2135
Polymers226,2823
Non-polymers9312
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 128139.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 46465.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: Protein Interleukin-1 receptor-associated kinase 4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 51676.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-A1CDC / (8R)-N-{3-(difluoromethyl)-1-[(1S,4R)-4-({4-[(3-{1-[(3S)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-4-yl}prop-2-yn-1-yl)oxy]piperidin-1-yl}methyl)cyclohexyl]-1H-pyrazol-4-yl}-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 865.927 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H49F2N11O6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: IRAK4:KT-474:CRBN-DDB1 ternary complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200067 / Symmetry type: POINT

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