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- PDB-4ztl: Irak4-inhibitor co-structure -

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Basic information

Entry
Database: PDB / ID: 4ztl
TitleIrak4-inhibitor co-structure
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / PHOSPHATASE / 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 / interleukin-1-mediated signaling pathway / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / toll-like receptor 4 signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / 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 / Interleukin-1 signaling / cytokine-mediated signaling pathway / 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 / 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 / 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-4S1 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.39 Å
AuthorsFischmann, T.O.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors.
Authors: Seganish, W.M. / Fischmann, T.O. / Sherborne, B. / Matasi, J. / Lavey, B. / McElroy, W.T. / Tulshian, D. / Tata, J. / Sondey, C. / Garlisi, C.G. / Devito, K. / Fossetta, J. / Lundell, D. / Niu, X.
History
DepositionMay 14, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)137,4878
Polymers135,8254
Non-polymers1,6624
Water1,946108
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3722
Polymers33,9561
Non-polymers4161
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)34,3722
Polymers33,9561
Non-polymers4161
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)34,3722
Polymers33,9561
Non-polymers4161
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)34,3722
Polymers33,9561
Non-polymers4161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)145.180, 139.390, 87.980
Angle α, β, γ (deg.)90.000, 125.930, 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: 33956.195 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) / Strain (production host): SF21
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-4S1 / (1R,2S,3R,5R)-3-{[5-(1,3-benzothiazol-2-yl)-2-(propylamino)pyrimidin-4-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diol


Mass: 415.509 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H25N5O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 53.65 % / Description: Thick plates
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 1.80 to 2.0 M Sodium Malonate, 0.2 M Sodium Acetate, 25 mM Hexamminecobalt(III)chloride, 0.05%w/v Pluronic-F-68

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 25, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→50 Å / Num. obs: 54999 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 58.34 Å2 / Rmerge(I) obs: 0.044 / Χ2: 0.91 / Net I/av σ(I): 22.14 / Net I/σ(I): 13.7 / Num. measured all: 180063
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
2.39-2.443.20.4772.327651.00999.9
2.44-2.493.20.36727660.98799.8
2.49-2.533.20.36527750.97999.9
2.53-2.593.20.31127870.98499.9
2.59-2.643.20.27327240.97999.9
2.64-2.73.30.22627900.96999.8
2.7-2.773.30.20327671.00999.9
2.77-2.853.30.15627720.96599.7
2.85-2.933.30.12527780.94699.9
2.93-3.023.30.09727470.95299.7
3.02-3.133.30.07727660.94699.7
3.13-3.263.30.06527960.91299.8
3.26-3.413.30.05327450.90799.4
3.41-3.583.30.04227610.90299.4
3.58-3.813.30.03527570.84599
3.81-4.13.30.02827500.82398.8
4.1-4.523.30.02627330.79798.6
4.52-5.173.30.02427460.74397.9
5.17-6.513.30.02427420.77897.9
6.51-503.10.02225320.74688.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.9.3refinement
PDB_EXTRACT3.15data extraction
Omodel building
BUSTER-TNTphasing
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2NRU

2nru


Resolution: 2.39→28.31 Å / Cor.coef. Fo:Fc: 0.9067 / Cor.coef. Fo:Fc free: 0.897 / SU R Cruickshank DPI: 0.376 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.351 / SU Rfree Blow DPI: 0.236 / SU Rfree Cruickshank DPI: 0.244
RfactorNum. reflection% reflectionSelection details
Rfree0.2508 2817 5.13 %RANDOM
Rwork0.2245 ---
obs0.2259 54881 98.04 %-
Displacement parametersBiso max: 209.81 Å2 / Biso mean: 76.16 Å2 / Biso min: 23.95 Å2
Baniso -1Baniso -2Baniso -3
1--11.0119 Å20 Å2-13.3075 Å2
2--16.6931 Å20 Å2
3----5.6813 Å2
Refine analyzeLuzzati coordinate error obs: 0.393 Å
Refinement stepCycle: final / Resolution: 2.39→28.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8836 0 224 0 9060
Biso mean--61.02 --
Num. residues----1128
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3204SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes260HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1279HARMONIC5
X-RAY DIFFRACTIONt_it9125HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1197SEMIHARMONIC5
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_contact10291SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9125HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12297HARMONIC21.15
X-RAY DIFFRACTIONt_omega_torsion2.47
X-RAY DIFFRACTIONt_other_torsion18.89
LS refinement shellResolution: 2.39→2.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3066 177 4.76 %
Rwork0.257 3540 -
all0.2594 3717 -
obs--98.04 %

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