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

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Basic information

Entry
Database: PDB / ID: 4ztn
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 / 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 / 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 / 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 / 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-4S3 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.23 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

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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)137,4758
Polymers135,8254
Non-polymers1,6504
Water2,900161
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3692
Polymers33,9561
Non-polymers4131
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)34,3692
Polymers33,9561
Non-polymers4131
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)34,3692
Polymers33,9561
Non-polymers4131
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)34,3692
Polymers33,9561
Non-polymers4131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.890, 139.180, 87.600
Angle α, β, γ (deg.)90.000, 125.280, 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-4S3 / 5-(1,3-benzothiazol-2-yl)-2-(morpholin-4-yl)-6-[(3R)-piperidin-3-ylamino]pyrimidin-4(3H)-one


Mass: 412.509 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H24N6O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.62 Å3/Da / Density % sol: 53.01 % / 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: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 3, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.225→37.449 Å / Num. obs: 67699 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 51.56 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 14.2 / Num. measured all: 226139
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique all% possible all
2.225-2.2333.40.483230667899.3
10.258-37.4493.30.02232369597.3

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Processing

Software
NameVersionClassification
SCALAdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.15data extraction
Omodel building
BUSTER-TNTphasing
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2NRU

2nru


Resolution: 2.23→37.449 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.9323 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.247 / SU Rfree Blow DPI: 0.18
RfactorNum. reflection% reflectionSelection details
Rfree0.2243 3411 5.07 %RANDOM
Rwork0.2089 ---
obs0.2097 67270 98.95 %-
Displacement parametersBiso max: 173.11 Å2 / Biso mean: 64.93 Å2 / Biso min: 27.5 Å2
Baniso -1Baniso -2Baniso -3
1--8.7347 Å20 Å2-4.3392 Å2
2--13.8549 Å20 Å2
3----5.1201 Å2
Refine analyzeLuzzati coordinate error obs: 0.327 Å
Refinement stepCycle: final / Resolution: 2.23→37.449 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9008 0 277 0 9285
Biso mean--58.12 --
Num. residues----1149
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4092SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes267HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2657HARMONIC5
X-RAY DIFFRACTIONt_it18193HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1205SEMIHARMONIC5
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_contact18803SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d18193HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg32854HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion15.87
LS refinement shellResolution: 2.23→2.29 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2373 246 4.92 %
Rwork0.225 4758 -
all0.2256 5004 -
obs--99.82 %

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