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

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Basic information

Entry
Database: PDB / ID: 6rfi
TitleIRAK4 IN COMPLEX WITH inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
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 / positive regulation of canonical NF-kappaB signal transduction / cellular response to lipopolysaccharide / endosome membrane / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / innate immune response / 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 / 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-K1H / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 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)74,0376
Polymers73,0562
Non-polymers9814
Water2,216123
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0193
Polymers36,5281
Non-polymers4912
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)37,0193
Polymers36,5281
Non-polymers4912
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.904, 116.781, 141.248
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11B-652-

HOH

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Components

#1: Protein Interleukin-1 receptor-associated kinase 4 / IRAK4 / 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-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-K1H / methyl 4-[4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate


Mass: 394.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26N6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / 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: 2.48 Å3/Da / Density % sol: 50.42 %
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 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.31→58.39 Å / Num. obs: 32155 / % possible obs: 100 % / Redundancy: 8.1 % / Biso Wilson estimate: 53.5 Å2 / Rmerge(I) obs: 0.073 / Net I/σ(I): 20.5
Reflection shellResolution: 2.31→2.44 Å / Redundancy: 8 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.6 PACIOREKrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.31→58.39 Å / Cor.coef. Fo:Fc: 0.9332 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.279 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.28 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.206
RfactorNum. reflection% reflectionSelection details
Rfree0.2365 1621 5.04 %RANDOM
Rwork0.2096 ---
obs0.2109 32151 99.75 %-
Displacement parametersBiso mean: 59.87 Å2
Baniso -1Baniso -2Baniso -3
1-3.7755 Å20 Å20 Å2
2---9.769 Å20 Å2
3---5.9936 Å2
Refine analyzeLuzzati coordinate error obs: 0.322 Å
Refinement stepCycle: LAST / Resolution: 2.31→58.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4371 0 68 123 4562
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014559HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.166152HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1649SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes135HARMONIC2
X-RAY DIFFRACTIONt_gen_planes670HARMONIC5
X-RAY DIFFRACTIONt_it4559HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion18.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion586SEMIHARMONIC5
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_contact5304SEMIHARMONIC4
LS refinement shellResolution: 2.31→2.39 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2357 127 4.49 %
Rwork0.2238 2703 -
all0.2244 2830 -
obs--97.43 %
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)
13.1103-0.72610.34111.7179-0.04452.14650.07760.18820.2593-0.06-0.13880.1802-0.0593-0.15450.0612-0.16870.0196-0.0289-0.1263-0.0039-0.1977-27.3497-28.3458-16.2687
22.0943-0.5270.37981.73030.52422.52340.16760.24960.02780.0116-0.154-0.17220.192-0.0213-0.0136-0.1304-0.00590.0188-0.09290.0417-0.258612.0544-33.1123-15.3383
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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