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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 / neutrophil migration / regulation of MAP kinase activity / negative regulation of monoatomic ion transmembrane transport / NLRP3 inflammasome complex assembly ...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 / neutrophil migration / regulation of MAP kinase activity / negative regulation of monoatomic ion transmembrane transport / NLRP3 inflammasome complex assembly / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / interleukin-1-mediated signaling pathway / epigenetic programming in the zygotic pronuclei / toll-like receptor 4 signaling pathway / IRAK4 deficiency (TLR2/4) / extrinsic component of plasma membrane / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / UV-damage excision repair / MyD88-dependent toll-like receptor signaling pathway / toll-like receptor signaling pathway / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / limb development / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / negative regulation of reproductive process / negative regulation of developmental process / Cul4B-RING E3 ubiquitin ligase complex / ectopic germ cell programmed cell death / ubiquitin ligase complex scaffold activity / locomotory exploration behavior / viral release from host cell / JNK cascade / cullin family protein binding / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / canonical NF-kappaB signal transduction / lipopolysaccharide-mediated signaling pathway / positive regulation of gluconeogenesis / positive regulation of smooth muscle cell proliferation / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / sperm end piece / sperm principal piece / nucleotide-excision repair / proteasomal protein catabolic process / positive regulation of protein-containing complex assembly / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / Wnt signaling pathway / DNA Damage Recognition in GG-NER / 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 / kinase activity / positive regulation of protein catabolic process / cellular response to UV / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / PIP3 activates AKT signaling / rhythmic process / sperm midpiece / site of double-strand break / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Neddylation / Potential therapeutics for SARS / damaged DNA binding / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / positive regulation of canonical NF-kappaB signal transduction / protein-macromolecule adaptor activity / chromosome, telomeric region / non-specific serine/threonine protein kinase / endosome membrane / intracellular signal transduction / protein ubiquitination / innate immune response / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / apoptotic process / DNA damage response / nucleolus / negative regulation of apoptotic process / protein kinase binding / protein-containing complex binding / perinuclear region of cytoplasm / magnesium ion binding / cell surface / protein-containing complex / DNA binding
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
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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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