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- PDB-5w85: CRYSTAL STRUCTURE OF IRAK-4 WITH A 4,6-DIAMINONICOTINAMIDE INHIBI... -

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Basic information

Entry
Database: PDB / ID: 5w85
TitleCRYSTAL STRUCTURE OF IRAK-4 WITH A 4,6-DIAMINONICOTINAMIDE INHIBITOR (COMPOUND NUMBER 9)
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / SERINE/THREONINE PROTEIN KINASE / TRANSFERASE / 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) / 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 / 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-9YS / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.25 Å
AuthorsSack, J.S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors.
Authors: Bhide, R.S. / Keon, A. / Weigelt, C. / Sack, J.S. / Schmidt, R.J. / Lin, S. / Xiao, H.Y. / Spergel, S.H. / Kempson, J. / Pitts, W.J. / Carman, J. / Poss, M.A.
History
DepositionJun 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,4124
Polymers68,5452
Non-polymers8672
Water1,928107
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7062
Polymers34,2731
Non-polymers4341
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)34,7062
Polymers34,2731
Non-polymers4341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.440, 125.560, 141.330
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Interleukin-1 receptor-associated kinase 4 / IRAK4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 34272.566 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 154-460
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-9YS / 6-[(1,3-benzothiazol-6-yl)amino]-4-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino}-N-methylpyridine-3-carboxamide


Mass: 433.526 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N5O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.86 Å3/Da / Density % sol: 57.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: Null

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 1, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 2.25→50 Å / Num. obs: 35556 / % possible obs: 93.9 % / Observed criterion σ(I): 0 / Redundancy: 7.9 % / Biso Wilson estimate: 48.75 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 34.9
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.352 / Mean I/σ(I) obs: 3.1 / % possible all: 72.2

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Processing

Software
NameVersionClassification
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
BUSTER2.11.7refinement
RefinementResolution: 2.25→29.72 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.91 / SU R Cruickshank DPI: 0.269 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.267 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.207
RfactorNum. reflection% reflectionSelection details
Rfree0.251 780 2.2 %RANDOM
Rwork0.227 ---
obs0.227 35437 94.1 %-
Displacement parametersBiso mean: 65.66 Å2
Baniso -1Baniso -2Baniso -3
1-9.584 Å20 Å20 Å2
2---24.2778 Å20 Å2
3---14.6937 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.25→29.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4353 0 126 107 4586
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014554HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.126149HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1607SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes131HARMONIC2
X-RAY DIFFRACTIONt_gen_planes693HARMONIC5
X-RAY DIFFRACTIONt_it4554HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion17.91
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion593SEMIHARMONIC5
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_contact5351SEMIHARMONIC4
LS refinement shellResolution: 2.25→2.31 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2696 -1.82 %
Rwork0.2528 2160 -
all0.2531 2200 -
obs--71.7 %

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