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- PDB-5kx8: Irak4-inhibitor co-structure -

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Basic information

Entry
Database: PDB / ID: 5kx8
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-6YE / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.671 Å
AuthorsFischmann, T.O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors.
Authors: Hanisak, J. / Seganish, W.M. / McElroy, W.T. / Tang, H. / Zhang, R. / Tsui, H.C. / Fischmann, T. / Tulshian, D. / Tata, J. / Sondey, C. / Devito, K. / Fossetta, J. / Garlisi, C.G. / Lundell, D. / Niu, X.
History
DepositionJul 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2016Group: Database references

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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)137,3028
Polymers135,8254
Non-polymers1,4784
Water48627
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3262
Polymers33,9561
Non-polymers3691
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)34,3262
Polymers33,9561
Non-polymers3691
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)34,3262
Polymers33,9561
Non-polymers3691
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)34,3262
Polymers33,9561
Non-polymers3691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.700, 139.880, 87.440
Angle α, β, γ (deg.)90.00, 125.25, 90.00
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: kinase domain (UNP residues 160-460)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Cell line (production host): SF21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-6YE / ~{N}-(3-aminocarbonyl-1-methyl-pyrazol-4-yl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 369.381 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H19N9O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 53.12 %
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: Dec 16, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.671→45 Å / Num. obs: 39609 / % possible obs: 99.7 % / Redundancy: 3.4 % / Biso Wilson estimate: 73.51 Å2 / Rmerge(I) obs: 0.05 / Rsym value: 0.05 / Net I/σ(I): 15.8
Reflection shellResolution: 2.671→2.68 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.576 / Mean I/σ(I) obs: 2.5 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSDecember 29, 2011data reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.671→45 Å / Cor.coef. Fo:Fc: 0.9119 / Cor.coef. Fo:Fc free: 0.9124 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.718 / SU Rfree Blow DPI: 0.286
RfactorNum. reflection% reflectionSelection details
Rfree0.2327 2015 5.09 %RANDOM
Rwork0.2041 ---
obs0.2056 39603 99.57 %-
Displacement parametersBiso mean: 80.08 Å2
Baniso -1Baniso -2Baniso -3
1--15.6518 Å20 Å2-15.0098 Å2
2--24.1361 Å20 Å2
3----8.4844 Å2
Refine analyzeLuzzati coordinate error obs: 0.377 Å
Refinement stepCycle: 1 / Resolution: 2.671→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17596 0 108 27 17731
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0118068HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0532610HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4057SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes266HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2654HARMONIC5
X-RAY DIFFRACTIONt_it18068HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion16.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1196SEMIHARMONIC5
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_contact18678SEMIHARMONIC4
LS refinement shellResolution: 2.67→2.74 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3075 156 5.46 %
Rwork0.2527 2702 -
all0.2555 2858 -
obs--99.57 %

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