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- PDB-6o8u: Crystal structure of IRAK4 in complex with compound 23 -

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Basic information

Entry
Database: PDB / ID: 6o8u
TitleCrystal structure of IRAK4 in complex with compound 23
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / inflammation / lupus / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-LS7 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsKiefer, J.R. / Yu, C. / Drobnick, J. / Bryan, M.C. / Lupardus, P.J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.
Authors: Bryan, M.C. / Drobnick, J. / Gobbi, A. / Kolesnikov, A. / Chen, Y. / Rajapaksa, N. / Ndubaku, C. / Feng, J. / Chang, W. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. / Ran, Y. / An, L. / ...Authors: Bryan, M.C. / Drobnick, J. / Gobbi, A. / Kolesnikov, A. / Chen, Y. / Rajapaksa, N. / Ndubaku, C. / Feng, J. / Chang, W. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. / Ran, Y. / An, L. / Emson, C. / Huang, Z. / Sujatha-Bhaskar, S. / Brightbill, H. / DiPasquale, A. / Maher, J. / Wai, J. / McKenzie, B.S. / Lupardus, P.J. / Zarrin, A.A. / Kiefer, J.R.
History
DepositionMar 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1May 29, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 24, 2019Group: Data collection / 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
C: Interleukin-1 receptor-associated kinase 4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,03214
Polymers136,8864
Non-polymers2,14610
Water8,179454
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8034
Polymers34,2221
Non-polymers5823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7113
Polymers34,2221
Non-polymers4902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7113
Polymers34,2221
Non-polymers4902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8074
Polymers34,2221
Non-polymers5863
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.119, 140.511, 87.518
Angle α, β, γ (deg.)90.000, 123.970, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Interleukin-1 receptor-associated kinase 4 / IRAK4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 34221.523 Da / Num. of mol.: 4 / Fragment: residues 160-460
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-LS7 / N-[2,2-dimethyl-6-(morpholin-4-yl)-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 393.439 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H23N5O3
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 454 / 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: 2.65 Å3/Da / Density % sol: 53.53 %
Crystal growTemperature: 292 K / Method: vapor diffusion
Details: 2.3M-2.7M ammonium sulfate, 0.1M HEPES Na pH 7.0-7.3
PH range: 7.0-7.3

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→35 Å / Num. obs: 116955 / % possible obs: 89.2 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.039 / Rrim(I) all: 0.076 / Χ2: 0.99 / Net I/σ(I): 9.5 / Num. measured all: 397651
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.8-1.833.40.69962520.5930.4340.8260.496.2
1.83-1.863.40.6163560.6850.3770.7210.41697.2
1.86-1.93.20.56359570.7430.3550.6690.42890.4
1.9-1.942.30.22631740.8860.1550.2753.55149
1.94-1.983.30.33763490.8870.210.3990.50696.5
1.98-2.033.40.27562830.9290.1710.3250.50996
2.03-2.083.30.23363120.9320.1470.2770.57896.5
2.08-2.133.10.18962160.9520.1220.2260.5995.2
2.13-2.230.15158330.9660.1010.1830.61688.9
2.2-2.272.70.1429570.960.0970.1711.85945
2.27-2.353.60.1257830.9840.0710.140.70588.9
2.35-2.443.70.10564360.9850.0610.1220.7998
2.44-2.553.70.0964140.9890.0530.1050.88498
2.55-2.693.60.07963780.990.0470.0920.95597.7
2.69-2.863.60.06963710.9920.0420.0811.07896.6
2.86-3.083.30.05860310.9940.0370.0691.26192.3
3.08-3.393.60.05461330.9950.0320.0631.54193.1
3.39-3.883.70.05153930.9950.030.0591.85282.2
3.88-4.883.60.04360680.9960.0260.051.74591.6
1.8-1.833.40.69962520.5930.4340.8260.496.2

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→35 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.931 / SU B: 8.147 / SU ML: 0.121 / SU R Cruickshank DPI: 0.1607 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.161 / ESU R Free: 0.143
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.255 5765 4.9 %RANDOM
Rwork0.231 ---
obs0.2321 111189 89.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 110.47 Å2 / Biso mean: 41.754 Å2 / Biso min: 8.89 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å2-0 Å20.62 Å2
2---1.9 Å20 Å2
3---0.4 Å2
Refinement stepCycle: final / Resolution: 1.8→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8980 0 147 458 9585
Biso mean--43.03 40.75 -
Num. residues----1151
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0199395
X-RAY DIFFRACTIONr_bond_other_d0.0020.028747
X-RAY DIFFRACTIONr_angle_refined_deg1.1451.99112739
X-RAY DIFFRACTIONr_angle_other_deg0.871320186
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.51951162
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.74225.333420
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.239151636
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6471537
X-RAY DIFFRACTIONr_chiral_restr0.0630.21419
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0210618
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022005
LS refinement shellResolution: 1.801→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 452 -
Rwork0.306 8807 -
all-9259 -
obs--95.33 %
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)
12.37120.112-0.81692.48350.65443.1469-0.10120.1036-0.2651-0.0999-0.02190.06450.2699-0.04690.1230.0691-0.00390.02130.0106-0.02770.076226.4425-4.31718.3287
22.20930.352-0.80692.302-0.92562.7431-0.1387-0.1585-0.46740.1512-0.0247-0.06210.3117-0.0720.16340.0754-0.01270.03740.02440.0370.131112.4613-3.508642.9267
32.37710.5761-0.66482.86070.05173.02210.04650.00250.13060.0862-0.0168-0.1389-0.27110.263-0.02980.056-0.03220.02960.03030.00060.06717.6297-35.280848.4718
42.1663-0.3999-0.38212.41470.33032.40440.0096-0.09330.1792-0.01750.04320.1814-0.3939-0.0745-0.05280.09780.00390.02970.0122-0.01170.051728.1259-36.0334-0.0842
53.54490.27441.50083.19451.3133.27050.0469-0.1563-0.50620.620.0429-0.7390.54530.5725-0.08980.24370.0456-0.06150.21770.07850.372447.7815.579616.529
63.9364-0.22451.10731.24080.03474.27610.06910.2898-0.3024-0.1224-0.11410.38820.3404-0.48210.0450.11410.02980.00510.2343-0.07620.214-7.867.554532.8862
72.4441.11070.90932.6766-0.54962.4325-0.05780.30630.3821-0.22790.11190.4627-0.3183-0.2041-0.05410.16390.0257-0.01280.1450.03910.1806-7.2874-44.510431.6247
83.2803-0.65120.88861.5029-0.3333.58610.0938-0.2210.15890.1395-0.0097-0.2751-0.20430.4496-0.08410.1093-0.04760.02480.16250.00830.108242.1182-48.287116.5543
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A269 - 458
2X-RAY DIFFRACTION2B269 - 458
3X-RAY DIFFRACTION3C269 - 458
4X-RAY DIFFRACTION4D269 - 458
5X-RAY DIFFRACTION5A162 - 268
6X-RAY DIFFRACTION6B162 - 268
7X-RAY DIFFRACTION7C162 - 268
8X-RAY DIFFRACTION8D162 - 268

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