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- PDB-5k7i: IRAK4 in complex with AZ3864 -

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Basic information

Entry
Database: PDB / ID: 5k7i
TitleIRAK4 in complex with AZ3864
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Kinase / Protein tyrosine kinase / 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 / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/Threonine protein kinases, catalytic domain ...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 / 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-6QZ / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7545
Polymers67,7522
Non-polymers1,0013
Water1,38777
1
A: 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
2
B: 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)87.540, 110.530, 142.420
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 33876.215 Da / Num. of mol.: 2 / 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-6QZ / (3~{a}~{R},7~{a}~{S})-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.: 2 / Source method: obtained synthetically / Formula: C25H36N6O2
#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.: 77 / 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: 2.55 Å3/Da / Density % sol: 51.85 %
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: 2.31→74.57 Å / Num. obs: 30450 / % possible obs: 99.1 % / Redundancy: 8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.073 / Net I/σ(I): 15.5
Reflection shellResolution: 2.31→2.32 Å / Redundancy: 8.1 % / Mean I/σ(I) obs: 2.3 / Num. measured obs: 303 / % possible all: 97.1

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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: 2.31→71.21 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.914 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.304 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.3 / SU Rfree Blow DPI: 0.225 / SU Rfree Cruickshank DPI: 0.228
RfactorNum. reflection% reflectionSelection details
Rfree0.257 1491 4.9 %RANDOM
Rwork0.219 ---
obs0.221 30401 99.1 %-
Displacement parametersBiso max: 193.5 Å2 / Biso mean: 85.67 Å2 / Biso min: 37.94 Å2
Baniso -1Baniso -2Baniso -3
1-1.3475 Å20 Å20 Å2
2---11.4471 Å20 Å2
3---10.0996 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.31→71.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4349 0 71 77 4497
Biso mean--63.48 57.75 -
Num. residues----547
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1633SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes127HARMONIC2
X-RAY DIFFRACTIONt_gen_planes622HARMONIC5
X-RAY DIFFRACTIONt_it4500HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion580SEMIHARMONIC5
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_contact5078SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4500HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6073HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion20.28
LS refinement shellResolution: 2.31→2.39 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.248 133 4.48 %
Rwork0.218 2839 -
all-2972 -
obs--100 %
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)
12.4013-0.6005-1.91061.51850.48496.865-0.2656-0.1754-0.18840.14230.134-0.19781.15970.86780.1316-0.02860.2430.0213-0.29250.019-0.4988-16.7511-30.6548-16.7598
23.6055-1.0205-2.45561.75430.87667.09190.62940.27090.0622-0.1191-0.25290.1692-0.3254-0.4636-0.37650.1615-0.07290.0166-0.2295-0.0383-0.3355-56.3771-24.629-15.0739
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A164 - 458
2X-RAY DIFFRACTION2{ B|* }B164 - 458

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