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- PDB-7qg3: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 7qg3
TitleIRAK4 in complex with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / Kinase inhibitor Interleukin-1 Receptor-Associated Kinase 4 Interleukin-1 signaling
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 / neutrophil migration / interleukin-33-mediated signaling pathway / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding ...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 / neutrophil migration / interleukin-33-mediated signaling pathway / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / MyD88-dependent toll-like receptor signaling pathway / interleukin-1-mediated signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / extrinsic component of plasma membrane / JNK cascade / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / PIP3 activates AKT signaling / kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cellular response to lipopolysaccharide / positive regulation of canonical NF-kappaB signal transduction / endosome membrane / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / cell surface / magnesium ion binding / extracellular space / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
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
Chem-B4U / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsXue, Y. / Aagaard, A. / Robb, G.R. / Degorce, S.L.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Other private Sweden
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.
Authors: Cumming, I.A. / Degorce, S.L. / Aagaard, A. / Braybrooke, E.L. / Davies, N.L. / Diene, C.R. / Eatherton, A.J. / Felstead, H.R. / Groombridge, S.D. / Lenz, E.M. / Li, Y. / Nai, Y. / Pearson, ...Authors: Cumming, I.A. / Degorce, S.L. / Aagaard, A. / Braybrooke, E.L. / Davies, N.L. / Diene, C.R. / Eatherton, A.J. / Felstead, H.R. / Groombridge, S.D. / Lenz, E.M. / Li, Y. / Nai, Y. / Pearson, S. / Robb, G.R. / Scott, J.S. / Steward, O.R. / Wu, C. / Xue, Y. / Zhang, L. / Zhang, Y.
History
DepositionDec 7, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,3394
Polymers69,4302
Non-polymers9092
Water54030
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1702
Polymers34,7151
Non-polymers4551
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)35,1702
Polymers34,7151
Non-polymers4551
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.330, 110.710, 142.320
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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


Mass: 34714.988 Da / Num. of mol.: 2
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-B4U / 6-[(2~{S})-2-fluoranylpropyl]-4-[(1-methylcyclopropyl)amino]-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one


Mass: 454.544 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H31FN8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.48 Å3/Da / Density % sol: 50.35 %
Crystal growTemperature: 298 K / Method: evaporation / Details: 2.7 M AMS 0.1 M Hepes pH 7.1-7.7

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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 PILATUS 6M / 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: 2.11→49.37 Å / Num. obs: 39631 / % possible obs: 99.5 % / Redundancy: 8.1 % / Biso Wilson estimate: 55.53 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.037 / Rrim(I) all: 0.093 / Net I/σ(I): 9.8
Reflection shellResolution: 2.11→2.19 Å / Redundancy: 5.9 % / Mean I/σ(I) obs: 0.7 / Num. unique obs: 3712 / CC1/2: 0.364 / % possible all: 95.4

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASESphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6RFJ

6rfj


Resolution: 2.11→44.42 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.285 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.277 / SU Rfree Blow DPI: 0.223 / SU Rfree Cruickshank DPI: 0.228
RfactorNum. reflection% reflectionSelection details
Rfree0.304 1886 5.05 %RANDOM
Rwork0.272 ---
obs0.273 37347 93.3 %-
Displacement parametersBiso max: 217.08 Å2 / Biso min: 29.54 Å2
Baniso -1Baniso -2Baniso -3
1--11.0638 Å20 Å20 Å2
2---7.3165 Å20 Å2
3---18.3803 Å2
Refine analyzeLuzzati coordinate error obs: 0.49 Å
Refinement stepCycle: final / Resolution: 2.11→44.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4452 0 66 30 4548
Biso mean--57.76 56.81 -
Num. residues----561
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1629SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes132HARMONIC2
X-RAY DIFFRACTIONt_gen_planes651HARMONIC5
X-RAY DIFFRACTIONt_it4598HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion595SEMIHARMONIC5
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_contact5052SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4598HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6213HARMONIC21.21
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion20.04
LS refinement shellResolution: 2.11→2.17 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2627 147 5.41 %
Rwork0.2458 2568 -
all0.2468 2715 -
obs--87.87 %

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