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- PDB-9r9j: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 9r9j
TitleIRAK4 in complex with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / inhibitor complex phosphorylation signal transduction
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 / toll-like receptor 9 signaling pathway / interleukin-1 receptor binding / neutrophil mediated immunity ...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 / toll-like receptor 9 signaling pathway / interleukin-1 receptor binding / neutrophil mediated immunity / interleukin-1-mediated signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / extrinsic component of plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / JNK cascade / positive regulation of smooth muscle cell proliferation / lipopolysaccharide-mediated signaling pathway / Interleukin-1 signaling / cytokine-mediated signaling pathway / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / endosome membrane / positive regulation of canonical NF-kappaB signal transduction / non-specific serine/threonine protein kinase / intracellular signal transduction / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / magnesium ion binding / cell surface / extracellular space / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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: 2.39 Å
AuthorsXue, Y. / Terstiege, I. / Aagaard, A.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Other private Sweden
CitationJournal: Bioorg.Med.Chem. / Year: 2025
Title: Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach.
Authors: Terstiege, I. / Aagaard, A. / Berggren, K. / Bird, J. / Cumming, I.A. / Groombridge, S.D. / Hidestal, L. / Johannesson, P. / Korsgren, P. / Leuchowius, K.J. / Lundqvist, S. / Scott, J.S. / ...Authors: Terstiege, I. / Aagaard, A. / Berggren, K. / Bird, J. / Cumming, I.A. / Groombridge, S.D. / Hidestal, L. / Johannesson, P. / Korsgren, P. / Leuchowius, K.J. / Lundqvist, S. / Scott, J.S. / Xue, Y. / Degorce, S.L.
History
DepositionMay 20, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 1, 2025Provider: 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)140,3908
Polymers138,5404
Non-polymers1,8504
Water7,963442
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0982
Polymers34,6351
Non-polymers4631
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)35,0982
Polymers34,6351
Non-polymers4631
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)35,0982
Polymers34,6351
Non-polymers4631
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)35,0982
Polymers34,6351
Non-polymers4631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)143.290, 140.240, 88.800
Angle α, β, γ (deg.)90.00, 124.06, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 34635.008 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-A1JDR / ~{N}-[2-(3-methyl-3-oxidanyl-butyl)-6-(2-oxidanylpropan-2-yl)indazol-5-yl]-1-(2-methylpyridin-4-yl)pyrazole-3-carboxamide


Mass: 462.544 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H30N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 442 / 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: 2.54 Å3/Da / Density % sol: 51.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 2.5 M AMS 0.1 M Hepes pH 6.9-7.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.39→90.6 Å / Num. obs: 56900 / % possible obs: 99.9 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.059 / Net I/σ(I): 11.9
Reflection shellResolution: 2.39→2.43 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.494 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2862 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7refinement
autoPROCdata scaling
PDB_EXTRACTdata extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.39→90 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.906 / SU R Cruickshank DPI: 0.379 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.376 / SU Rfree Blow DPI: 0.254 / SU Rfree Cruickshank DPI: 0.258
RfactorNum. reflection% reflectionSelection details
Rfree0.263 2780 4.89 %RANDOM
Rwork0.221 ---
obs0.223 56895 99.1 %-
Displacement parametersBiso mean: 53.57 Å2
Baniso -1Baniso -2Baniso -3
1--8.3951 Å20 Å2-6.2657 Å2
2--10.2567 Å20 Å2
3----1.8617 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.39→90 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8921 0 220 442 9583
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019300HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1912571HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3301SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes269HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1340HARMONIC5
X-RAY DIFFRACTIONt_it9300HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion18.81
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1203SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10717SEMIHARMONIC4
LS refinement shellResolution: 2.39→2.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2913 197 4.69 %
Rwork0.2363 4005 -
all0.2389 4202 -
obs--99.79 %

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