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- PDB-5k7g: IRAK4 in complex with AZ3862 -

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Basic information

Entry
Database: PDB / ID: 5k7g
TitleIRAK4 in complex with AZ3862
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Kinase / Protein tyrosine kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding ...MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / interleukin-1-mediated signaling pathway / MyD88-dependent toll-like receptor 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 / 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 / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6R0 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 Å
AuthorsFerguson, A.D.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma.
Authors: Scott, J.S. / Degorce, S.L. / Anjum, R. / Culshaw, J. / Davies, R.D.M. / Davies, N.L. / Dillman, K.S. / Dowling, J.E. / Drew, L. / Ferguson, A.D. / Groombridge, S.D. / Halsall, C.T. / ...Authors: Scott, J.S. / Degorce, S.L. / Anjum, R. / Culshaw, J. / Davies, R.D.M. / Davies, N.L. / Dillman, K.S. / Dowling, J.E. / Drew, L. / Ferguson, A.D. / Groombridge, S.D. / Halsall, C.T. / Hudson, J.A. / Lamont, S. / Lindsay, N.A. / Marden, S.K. / Mayo, M.F. / Pease, J.E. / Perkins, D.R. / Pink, J.H. / Robb, G.R. / Rosen, A. / Shen, M. / McWhirter, C. / Wu, D.
History
DepositionMay 26, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2018Group: 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
Revision 1.2Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)137,79613
Polymers135,5054
Non-polymers2,2919
Water5,639313
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5214
Polymers33,8761
Non-polymers6453
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)34,5214
Polymers33,8761
Non-polymers6453
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3292
Polymers33,8761
Non-polymers4531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4253
Polymers33,8761
Non-polymers5492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.214, 140.995, 86.845
Angle α, β, γ (deg.)90.000, 126.190, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 33876.215 Da / Num. of mol.: 4 / Fragment: UNP 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-6R0 / (3~{a}~{S},7~{a}~{R})-1-methyl-5-[4-[[5-(oxan-4-yl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]-3,3~{a},4,6,7,7~{a}-hexahydropyrrolo[3,2-c]pyridin-2-one


Mass: 452.592 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H36N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.51 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.2 / Details: 2.5 M ammonium sulfate, 0.1 M Hepes / PH range: 6.8-7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.10406 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 27, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.10406 Å / Relative weight: 1
ReflectionResolution: 2.23→45.29 Å / Num. obs: 61883 / % possible obs: 95.8 % / Redundancy: 4 % / CC1/2: 0.995 / Rmerge(I) obs: 0.104 / Net I/σ(I): 10
Reflection shellResolution: 2.23→2.24 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.685 / Mean I/σ(I) obs: 2.2 / % possible all: 89.9

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.7refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NRU

2nru


Resolution: 2.23→45.29 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.908 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.288 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.279 / SU Rfree Blow DPI: 0.195 / SU Rfree Cruickshank DPI: 0.199
RfactorNum. reflection% reflectionSelection details
Rfree0.227 3037 4.91 %RANDOM
Rwork0.206 ---
obs0.207 61845 95.5 %-
Displacement parametersBiso max: 148.35 Å2 / Biso mean: 47.04 Å2 / Biso min: 18.4 Å2
Baniso -1Baniso -2Baniso -3
1--3.6626 Å20 Å2-2.7483 Å2
2--8.7782 Å20 Å2
3----5.1156 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 2.23→45.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8881 0 157 314 9352
Biso mean--48.16 42.28 -
Num. residues----1124
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3333SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes268HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1277HARMONIC5
X-RAY DIFFRACTIONt_it9200HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1192SEMIHARMONIC5
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_contact10671SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9200HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg12427HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion2.35
X-RAY DIFFRACTIONt_other_torsion18.17
LS refinement shellResolution: 2.23→2.29 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 101 3.68 %
Rwork0.247 2640 -
all-2741 -
obs--57.42 %
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)
11.07550.5014-0.17461.80450.09371.9391-0.01890.1538-0.0172-0.03540.0172-0.1041-0.2852-0.00380.0017-0.10070.00360.0396-0.17920.0144-0.151934.65316.342-6.304
21.6006-0.337-0.09291.5762-0.27771.3095-0.0213-0.0543-0.12310.07550.01990.06270.003-0.16160.0013-0.1408-0.00710.0462-0.14270.0076-0.12793.216-16.45937.642
32.30030.7518-0.06281.44410.36531.05-0.08990.1054-0.3044-0.06460.0486-0.08250.12390.02050.0414-0.09530.02090.0423-0.201-0.0169-0.111331.093-15.5559.175
41.0666-0.45810.44511.1774-0.82412.9973-0.0315-0.07730.02230.17260.10780.1093-0.4388-0.1773-0.0763-0.06930.03360.0486-0.2116-0.0115-0.116915.48915.59628.937
50.15530.2231-0.28460.0531-0.24780.4878-0.04410.1023-0.0319-0.05810.04850.0295-0.056-0.1239-0.0043-0.05230-0.02130.0168-0.0229-0.002620.914-0.08317.269
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|164 - A|458 }A164 - 458
2X-RAY DIFFRACTION2{ B|165 - B|458 }B165 - 458
3X-RAY DIFFRACTION3{ C|164 - C|458 }C164 - 458
4X-RAY DIFFRACTION4{ D|164 - D|458 }D164 - 458
5X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|503 - B|503 D|502 - D|502 }A503
6X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|503 - B|503 D|502 - D|502 }C501
7X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|503 - B|503 D|502 - D|502 }B503
8X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|503 - B|503 D|502 - D|502 }D502

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