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- PDB-9opk: Crystal structure of IRAK4 with compound 1, an analog of KT-474 TBM -

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Entry
Database: PDB / ID: 9opk
TitleCrystal structure of IRAK4 with compound 1, an analog of KT-474 TBM
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / Kinase / inhibitor / heterobifunctional degrader
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 / NLRP3 inflammasome complex assembly / toll-like receptor 9 signaling pathway ...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 / NLRP3 inflammasome complex assembly / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / interleukin-1-mediated signaling pathway / toll-like receptor 4 signaling pathway / IRAK4 deficiency (TLR2/4) / extrinsic component of plasma membrane / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / MyD88-dependent toll-like receptor signaling pathway / toll-like receptor signaling pathway / JNK cascade / canonical NF-kappaB signal transduction / lipopolysaccharide-mediated signaling pathway / positive regulation of smooth muscle cell proliferation / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / cytokine-mediated signaling pathway / Interleukin-1 signaling / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of canonical NF-kappaB signal transduction / non-specific serine/threonine protein kinase / endosome membrane / intracellular signal transduction / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / magnesium ion binding / cell surface / : / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Death-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-1 receptor-associated kinase 4
B: Interleukin-1 receptor-associated kinase 4
C: Interleukin-1 receptor-associated kinase 4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,40723
Polymers136,9104
Non-polymers2,49719
Water8,665481
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7284
Polymers34,2281
Non-polymers5013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8826
Polymers34,2281
Non-polymers6555
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9147
Polymers34,2281
Non-polymers6876
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8826
Polymers34,2281
Non-polymers6555
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.603, 121.700, 140.424
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein
Interleukin-1 receptor-associated kinase 4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 34227.504 Da / Num. of mol.: 4
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
#2: Chemical
ChemComp-A1CDD / (8R)-N-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 376.364 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18F2N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 481 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.73 Å3/Da / Density % sol: 55.01 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5 / Details: 50mM HEPES, pH 7.5, 100mM NaCl, 5mM DTT

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2018
RadiationProtocol: MAD / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.05→41.32 Å / Num. obs: 94061 / % possible obs: 100 % / Redundancy: 6.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.017 / Rrim(I) all: 0.043 / Net I/σ(I): 28.8
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.878 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 8908 / CC1/2: 0.782 / CC star: 0.937 / Rpim(I) all: 0.379 / Rrim(I) all: 0.957 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
SCALAdata scaling
HKL-3000data reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→41.28 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.959 / SU B: 6.401 / SU ML: 0.081 / Cross valid method: THROUGHOUT / ESU R Free: 0.031 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2063 4827 5.1 %RANDOM
Rwork0.1576 ---
obs0.16008 89234 99.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.771 Å2
Baniso -1Baniso -2Baniso -3
1--19.56 Å2-0 Å2-0 Å2
2--47.72 Å20 Å2
3----28.16 Å2
Refinement stepCycle: 1 / Resolution: 2.05→41.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9312 0 172 481 9965
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0139681
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178966
X-RAY DIFFRACTIONr_angle_refined_deg1.2571.66113068
X-RAY DIFFRACTIONr_angle_other_deg1.1961.5920897
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.06251184
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.04324.107487
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.561151734
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.5251541
X-RAY DIFFRACTIONr_chiral_restr0.0520.21262
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0210698
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021845
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.6214.5994721
X-RAY DIFFRACTIONr_mcbond_other3.6174.5984720
X-RAY DIFFRACTIONr_mcangle_it4.5566.8945889
X-RAY DIFFRACTIONr_mcangle_other4.5566.8955890
X-RAY DIFFRACTIONr_scbond_it4.2165.1694960
X-RAY DIFFRACTIONr_scbond_other4.2165.174961
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3217.5457173
X-RAY DIFFRACTIONr_long_range_B_refined5.75255.02110759
X-RAY DIFFRACTIONr_long_range_B_other5.75255.02510760
X-RAY DIFFRACTIONr_rigid_bond_restr1.269318647
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.051→2.105 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 320 -
Rwork0.235 6134 -
obs--93.7 %

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