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- PDB-4y73: Crystal structure of IRAK4 kinase domain with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4y73
TitleCrystal structure of IRAK4 kinase domain with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE / Kinase / Inhibitor
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-XPY / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.14 Å
AuthorsLesburg, C.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.
Authors: Lim, J. / Altman, M.D. / Baker, J. / Brubaker, J.D. / Chen, H. / Chen, Y. / Fischmann, T. / Gibeau, C. / Kleinschek, M.A. / Leccese, E. / Lesburg, C. / Maclean, J.K. / Moy, L.Y. / Mulrooney, ...Authors: Lim, J. / Altman, M.D. / Baker, J. / Brubaker, J.D. / Chen, H. / Chen, Y. / Fischmann, T. / Gibeau, C. / Kleinschek, M.A. / Leccese, E. / Lesburg, C. / Maclean, J.K. / Moy, L.Y. / Mulrooney, E.F. / Presland, J. / Rakhilina, L. / Smith, G.F. / Steinhuebel, D. / Yang, R.
History
DepositionFeb 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 15, 2015Group: Database references

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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)137,7438
Polymers136,0534
Non-polymers1,6904
Water7,116395
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4362
Polymers34,0131
Non-polymers4221
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)34,4362
Polymers34,0131
Non-polymers4221
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)34,4362
Polymers34,0131
Non-polymers4221
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)34,4362
Polymers34,0131
Non-polymers4221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)142.860, 138.750, 88.020
Angle α, β, γ (deg.)90.00, 124.59, 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: 34013.246 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: unidentified baculovirus
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-XPY / 5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 422.408 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H21F3N8O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 395 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.64 Å3/Da / Density % sol: 53.4 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 0.03 M hexammine cobalt (III) chloride 0.2 M sodium acetate 0.05 w/v pluronic F-68 1.9 M sodium malonate pH 6.4

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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: Jun 7, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.14→74.24 Å / Num. obs: 76998 / % possible obs: 99.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 43.12 Å2 / Rmerge(I) obs: 0.055 / Net I/σ(I): 12.9
Reflection shellResolution: 2.14→2.31 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.416 / Mean I/σ(I) obs: 2.5 / % possible all: 89.4

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.14→74.24 Å / Cor.coef. Fo:Fc: 0.9292 / Cor.coef. Fo:Fc free: 0.9162 / SU R Cruickshank DPI: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.207 / SU Rfree Blow DPI: 0.162 / SU Rfree Cruickshank DPI: 0.165
RfactorNum. reflection% reflectionSelection details
Rfree0.2175 3869 5.02 %RANDOM
Rwork0.1953 ---
obs0.1964 76998 99.18 %-
Displacement parametersBiso mean: 55.82 Å2
Baniso -1Baniso -2Baniso -3
1--9.006 Å20 Å2-9.4819 Å2
2--14.1768 Å20 Å2
3----5.1708 Å2
Refine analyzeLuzzati coordinate error obs: 0.279 Å
Refinement stepCycle: 1 / Resolution: 2.14→74.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9101 0 120 395 9616
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019515HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1412876HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3394SINUSOIDAL2
LS refinement shellResolution: 2.14→2.2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2657 255 4.61 %
Rwork0.231 5277 -
all0.2325 5532 -
obs--99.18 %

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