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- PDB-5k75: IRAK4 in complex with Compound 1 -

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Basic information

Entry
Database: PDB / ID: 5k75
TitleIRAK4 in complex with Compound 1
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 / non-specific serine/threonine protein kinase / endosome membrane / 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-6QX / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.03 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 25, 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)137,44315
Polymers135,5054
Non-polymers1,93811
Water7,314406
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1932
Polymers33,8761
Non-polymers3161
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)34,4815
Polymers33,8761
Non-polymers6054
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)34,3854
Polymers33,8761
Non-polymers5093
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)34,3854
Polymers33,8761
Non-polymers5093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)144.870, 141.620, 88.060
Angle α, β, γ (deg.)90.000, 125.920, 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-6QX / ~{N}1-(7,8-dihydro-6~{H}-cyclopenta[2,3]thieno[2,4-~{c}]pyrimidin-1-yl)-~{N}4,~{N}4-dimethyl-cyclohexane-1,4-diamine


Mass: 316.464 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C17H24N4S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 406 / 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: 2.69 Å3/Da / Density % sol: 54.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 2.5 ammonium sulfate, 0.1 M Hepes pH 7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.03→58.86 Å / Num. obs: 89974 / % possible obs: 97 % / Redundancy: 4.8 % / Biso Wilson estimate: 49.31 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.038 / Net I/σ(I): 20.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.03-2.144.90.699189.3
6.42-45.184.50.022199.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.7refinement
Aimless0.5.23data scaling
MOLREPphasing
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NRU

2nru


Resolution: 2.03→45.18 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.926 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.207 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.204 / SU Rfree Blow DPI: 0.165 / SU Rfree Cruickshank DPI: 0.167
RfactorNum. reflection% reflectionSelection details
Rfree0.253 4487 5 %RANDOM
Rwork0.239 ---
obs0.24 89818 97 %-
Displacement parametersBiso max: 168.3 Å2 / Biso mean: 64.42 Å2 / Biso min: 27.25 Å2
Baniso -1Baniso -2Baniso -3
1--3.912 Å20 Å2-6.2256 Å2
2--6.9101 Å20 Å2
3----2.9981 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.03→45.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8844 0 123 409 9376
Biso mean--63.92 52.81 -
Num. residues----1115
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3261SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes268HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1281HARMONIC5
X-RAY DIFFRACTIONt_it9166HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1187SEMIHARMONIC5
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_contact11006SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9166HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12384HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion19.3
LS refinement shellResolution: 2.03→2.08 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 270 5.02 %
Rwork0.264 5104 -
all-5374 -
obs--78.8 %
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)
12.39560.5364-0.73562.0935-0.2583.8768-0.14340.59020.1204-0.31590.218-0.0884-0.34880.0559-0.0746-0.2968-0.10050.0192-0.24770.0232-0.408338.138716.4716-5.8286
23.50330.6752-0.92282.2647-0.39972.2148-0.0097-0.1675-0.26280.17030.00320.09460.1095-0.44820.0065-0.3544-0.03490.0157-0.28320.0628-0.32434.5132-16.000638.6045
32.31770.0689-0.21912.1258-0.13611.683-0.09150.3123-0.3904-0.2195-0.0199-0.18490.15110.09160.1114-0.29940.00620.0491-0.363-0.0898-0.225334.2295-15.33910.3441
41.5662-0.11830.13961.42720.30083.2918-0.0327-0.16440.0460.13060.06750.1023-0.4351-0.3486-0.0348-0.20320.07420.0245-0.3764-0.0206-0.302219.123816.029130.5786
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A164 - 458
2X-RAY DIFFRACTION2{ B|* }B163 - 458
3X-RAY DIFFRACTION3{ C|* }C164 - 458
4X-RAY DIFFRACTION4{ D|* }D164 - 458

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