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- PDB-8tx0: IRAK4 in complex with compound -

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Basic information

Entry
Database: PDB / ID: 8tx0
TitleIRAK4 in complex with compound
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/INHIBITOR / kinase / 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 / cytokine-mediated signaling pathway / Interleukin-1 signaling / PIP3 activates AKT signaling / kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cellular response to lipopolysaccharide / positive regulation of canonical NF-kappaB signal transduction / 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 / cell surface / magnesium ion binding / extracellular space / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
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 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMetrick, C.M. / Chodaparambil, J.V.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.
Authors: Pfaffenbach, M. / Bolduc, P.N. / Xin, Z. / Gao, F. / Evans, R. / Fang, T. / Chodaparambil, J.V. / Henry, K.L. / Li, P. / Mathieu, S. / Metrick, C. / Vera Rebollar, J.A. / Gu, R.F. / Mccarl, ...Authors: Pfaffenbach, M. / Bolduc, P.N. / Xin, Z. / Gao, F. / Evans, R. / Fang, T. / Chodaparambil, J.V. / Henry, K.L. / Li, P. / Mathieu, S. / Metrick, C. / Vera Rebollar, J.A. / Gu, R.F. / Mccarl, C.A. / Silbereis, J. / Peterson, E.A.
History
DepositionAug 21, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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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)70,4869
Polymers69,3162
Non-polymers1,1707
Water3,999222
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2324
Polymers34,6581
Non-polymers5743
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)35,2555
Polymers34,6581
Non-polymers5974
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.510, 118.910, 139.300
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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


Mass: 34657.938 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VEU / ~{N}-(1-cyclopropyl-2-oxidanylidene-pyridin-3-yl)-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxy-imidazo[1,2-a]pyrimidine-6-carboxamide


Mass: 449.502 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 222 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.81 Å3/Da / Density % sol: 56.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: sodium malonate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 1M / Detector: PIXEL / Date: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 96458 / % possible obs: 99.3 % / Redundancy: 3.38 % / Biso Wilson estimate: 40.24 Å2 / CC1/2: 0.998 / Net I/σ(I): 10.43
Reflection shellResolution: 2→2.12 Å / Num. unique obs: 15584 / CC1/2: 0.561

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→46.66 Å / SU ML: 0.2677 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.505
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2383 2521 5 %
Rwork0.2065 47899 -
obs0.2081 50420 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.35 Å2
Refinement stepCycle: LAST / Resolution: 2→46.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4457 0 83 222 4762
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074619
X-RAY DIFFRACTIONf_angle_d1.03186263
X-RAY DIFFRACTIONf_chiral_restr0.0575710
X-RAY DIFFRACTIONf_plane_restr0.0062795
X-RAY DIFFRACTIONf_dihedral_angle_d16.7241729
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.040.3611390.34572634X-RAY DIFFRACTION99.93
2.04-2.080.3441400.30072647X-RAY DIFFRACTION99.96
2.08-2.130.24741370.26242614X-RAY DIFFRACTION99.89
2.13-2.170.30621390.25472631X-RAY DIFFRACTION99.93
2.17-2.230.24751380.23472618X-RAY DIFFRACTION99.93
2.23-2.290.28911390.23882650X-RAY DIFFRACTION99.89
2.29-2.360.26511390.21562638X-RAY DIFFRACTION100
2.36-2.430.25381390.21362648X-RAY DIFFRACTION99.96
2.43-2.520.27231380.21772625X-RAY DIFFRACTION99.96
2.52-2.620.27351410.23462672X-RAY DIFFRACTION99.96
2.62-2.740.30941390.23052630X-RAY DIFFRACTION99.96
2.74-2.880.26031390.22712649X-RAY DIFFRACTION99.75
2.88-3.060.20371410.20962672X-RAY DIFFRACTION99.72
3.07-3.30.23181400.21062660X-RAY DIFFRACTION99.93
3.3-3.630.24441410.19582685X-RAY DIFFRACTION99.96
3.63-4.160.20591410.17612685X-RAY DIFFRACTION99.96
4.16-5.240.20881440.1742718X-RAY DIFFRACTION99.69
5.24-46.660.22371470.20552823X-RAY DIFFRACTION99.53

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