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- PDB-7qg1: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 7qg1
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 / phosphorylation / 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 / 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-B8I / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 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

Downloads & links

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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)74,0974
Polymers73,0562
Non-polymers1,0412
Water4,306239
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0492
Polymers36,5281
Non-polymers5211
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)37,0492
Polymers36,5281
Non-polymers5211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.739, 109.425, 142.335
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: 36528.082 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-B8I / methyl 4-[4-[[6-(cyanomethyl)-2-[(1-methylpyrazol-4-yl)amino]-5-oxidanylidene-pyrido[4,3-d]pyrimidin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate


Mass: 520.587 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N10O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / 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: 2.34 Å3/Da / Density % sol: 47.39 %
Crystal growTemperature: 298 K / Method: evaporation / Details: Ammonium sulfate 0.1 M Hepes pH 6.8-7.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→86.75 Å / Num. obs: 41936 / % possible obs: 99.9 % / Redundancy: 7.8 % / Biso Wilson estimate: 48.53 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 16.3
Reflection shellResolution: 2.07→2.18 Å / Redundancy: 6.5 % / Rmerge(I) obs: 1.266 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 6032 / % possible all: 99.4

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6RFJ

6rfj


Resolution: 2.07→86.75 Å / Cor.coef. Fo:Fc: 0.909 / Cor.coef. Fo:Fc free: 0.898 / Rfactor Rfree error: 0.2 / SU R Cruickshank DPI: 0.228 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.233 / SU Rfree Blow DPI: 0.197 / SU Rfree Cruickshank DPI: 0.196
RfactorNum. reflection% reflectionSelection details
Rfree0.285 2118 5.06 %RANDOM
Rwork0.247 ---
obs0.249 41869 99.5 %-
Displacement parametersBiso max: 192.6 Å2 / Biso mean: 68.73 Å2 / Biso min: 27.89 Å2
Baniso -1Baniso -2Baniso -3
1--12.3351 Å20 Å20 Å2
2---5.6791 Å20 Å2
3---18.0142 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 2.07→86.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4342 0 76 239 4657
Biso mean--47.74 62.33 -
Num. residues----548
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1591SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes129HARMONIC2
X-RAY DIFFRACTIONt_gen_planes639HARMONIC5
X-RAY DIFFRACTIONt_it4498HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion575SEMIHARMONIC5
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_contact5312SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4498HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6069HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion20.3
LS refinement shellResolution: 2.07→2.12 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 152 5 %
Rwork0.256 2888 -
all0.256 3040 -
obs--98.64 %

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