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- PDB-6rfj: IRAK4 IN COMPLEX WITH inhibitor -

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Basic information

Entry
Database: PDB / ID: 6rfj
TitleIRAK4 IN COMPLEX WITH inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsSIGNALING PROTEIN / IRAK4 / kinase / inhibitor / cancer
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-K1E / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsXue, Y. / Degorce, S.L. / Robb, G.R. / Ferguson, A.D.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265PMutant Diffuse Large B Cell Lymphoma.
Authors: Degorce, S.L. / Anjum, R. / Bloecher, A. / Carbajo, R.J. / Dillman, K.S. / Drew, L. / Halsall, C.T. / Lenz, E.M. / Lindsay, N.A. / Mayo, M.F. / Pink, J.H. / Robb, G.R. / Rosen, A. / Scott, J.S. / Xue, Y.
History
DepositionApr 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name

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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)74,1615
Polymers73,0562
Non-polymers1,1053
Water43224
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0332
Polymers36,5281
Non-polymers5051
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)37,1293
Polymers36,5281
Non-polymers6012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.607, 118.925, 140.507
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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-K1E / methyl 4-[4-[[6-(cyanomethyl)-2-[(1-methylpyrazol-4-yl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate


Mass: 504.587 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N10O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O

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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: 2.56 Å3/Da / Density % sol: 51.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: pH7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.00001 / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.61→74.34 Å / Num. obs: 22141 / % possible obs: 98 % / Redundancy: 10.5 % / Biso Wilson estimate: 71.12 Å2 / Rmerge(I) obs: 0.091 / Net I/σ(I): 16.8
Reflection shellResolution: 2.61→2.76 Å / Redundancy: 9.8 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 0 / % possible all: 86.7

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.6 PACIOREKrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→28.34 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.662 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.64 / SU Rfree Blow DPI: 0.294 / SU Rfree Cruickshank DPI: 0.3
RfactorNum. reflection% reflectionSelection details
Rfree0.254 1084 4.92 %RANDOM
Rwork0.245 ---
obs0.245 22012 97 %-
Displacement parametersBiso mean: 92.06 Å2
Baniso -1Baniso -2Baniso -3
1-2.5329 Å20 Å20 Å2
2---9.6083 Å20 Å2
3---7.0754 Å2
Refine analyzeLuzzati coordinate error obs: 0.46 Å
Refinement stepCycle: LAST / Resolution: 2.61→28.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4305 0 121 24 4450
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014505HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.216076HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1626SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes131HARMONIC2
X-RAY DIFFRACTIONt_gen_planes622HARMONIC5
X-RAY DIFFRACTIONt_it4505HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.78
X-RAY DIFFRACTIONt_other_torsion19.81
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion574SEMIHARMONIC5
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_contact5157SEMIHARMONIC4
LS refinement shellResolution: 2.61→2.74 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.316 103 4.25 %
Rwork0.301 2323 -
all0.302 2426 -
obs--81.45 %
Refinement TLS params.

Method: refined / 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)
13.2294-0.7327-1.0712.0584-0.45574.97360.29180.0383-0.3687-0.2063-0.3982-0.3668-1.04741.13530.10650.4561-0.4673-0.0340.17480.0618-0.452-16.3492-31.3487-15.8118
21.9061-1.10520.85982.6001-0.71346.6883-0.05610.2325-0.10850.0775-0.13180.2558-1.5959-0.36870.18790.60220.2395-0.0798-0.2708-0.0648-0.5478-55.5644-25.9321-15.5163
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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