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- PDB-7qg5: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 7qg5
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-B7R / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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)70,2154
Polymers69,2702
Non-polymers9452
Water3,459192
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1082
Polymers34,6351
Non-polymers4731
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)35,1082
Polymers34,6351
Non-polymers4731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.4, 110.38, 142.11
Angle α, β, γ (deg.)90, 90, 90
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: 34635.008 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-B7R / 4-[(1-methylcyclopropyl)amino]-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]-6-pyrimidin-5-yl-pyrido[4,3-d]pyrimidin-5-one


Mass: 472.546 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N10O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.47 Å3/Da / Density % sol: 50.28 %
Crystal growTemperature: 298 K / Method: evaporation / Details: 2.5 M AMS 0.1 M Hepes pH 7.45

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Feb 17, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.3→86.88 Å / Num. obs: 30396 / % possible obs: 98.9 % / Redundancy: 6.6 % / CC1/2: 0.997 / Net I/σ(I): 9.6
Reflection shellResolution: 2.3→2.34 Å / Mean I/σ(I) obs: 2.3 / Num. unique obs: 1512 / CC1/2: 0.858 / % possible all: 99.1

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
Aimlessdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6RFJ

6rfj


Resolution: 2.3→68.52 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.359 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.369 / SU Rfree Blow DPI: 0.248 / SU Rfree Cruickshank DPI: 0.248
RfactorNum. reflection% reflectionSelection details
Rfree0.275 1472 -RANDOM
Rwork0.2473 ---
obs0.2486 30303 98 %-
Displacement parametersBiso mean: 69.71 Å2
Baniso -1Baniso -2Baniso -3
1--5.1291 Å20 Å20 Å2
2---5.9319 Å20 Å2
3---11.061 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: LAST / Resolution: 2.3→68.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4376 0 70 192 4638
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084534HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.026124HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1608SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes781HARMONIC5
X-RAY DIFFRACTIONt_it4534HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion583SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3745SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion18.44
LS refinement shellResolution: 2.3→2.32 Å
RfactorNum. reflection% reflection
Rfree0.3337 25 -
Rwork0.3141 --
obs0.3148 607 99.2 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.2105-0.5797-1.16250.79590.63134.6468-0.06080.04960.79590.04960.02830.56160.79590.56160.03250.10480.20590.0140.09640.0413-0.1175-16.8378-30.0679-16.8363
21.1905-0.9071-0.70280.99820.22833.87870.3476-0.0696-0.1115-0.0696-0.1968-0.2263-0.1115-0.2263-0.15080.0512-0.0291-0.00650.0225-0.0802-0.1696-56.0908-25.1688-15.412
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A165 - 458
2X-RAY DIFFRACTION2{ B|* }B164 - 458

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