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- PDB-9na2: IRAK4 in Complex with Compound 9 -

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Basic information

Entry
Database: PDB / ID: 9na2
TitleIRAK4 in Complex with Compound 9
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsIMMUNE SYSTEM / TRANSFERASE/INHIBITOR / Kinase / Phosphorylated / Signaling Protein / Inhibitor Complex / 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 / interleukin-33-mediated signaling pathway / neutrophil migration / 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 / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / interleukin-1-mediated signaling pathway / extrinsic component of plasma membrane / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / JNK cascade / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of canonical NF-kappaB signal transduction / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / endosome membrane / intracellular signal transduction / 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 / cytosol / cytoplasm
Similarity search - Function
Interleukin-1 receptor-associated kinase 4 / IRAK4, Death domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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: 1.99 Å
AuthorsFerrao, R. / Lansdon, E.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: J.Med.Chem. / Year: 2025
Title: Discovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4.
Authors: Ammann, S.E. / Cottell, J.J. / Wright, N.E. / Warr, M.R. / Snyder, C.A. / Bacon, E.M. / Brizgys, G. / Chin, E. / Chou, C. / Conway, A. / Dick, R.A. / Ferrao, R.D. / Garrison, K.L. / Hammond, ...Authors: Ammann, S.E. / Cottell, J.J. / Wright, N.E. / Warr, M.R. / Snyder, C.A. / Bacon, E.M. / Brizgys, G. / Chin, E. / Chou, C. / Conway, A. / Dick, R.A. / Ferrao, R.D. / Garrison, K.L. / Hammond, A. / Lansdon, E.B. / Link, J.O. / Mukherjee, P.K. / Murray, B.P. / Mwangi, J. / Ndukwe, M.S. / Park, G.Y. / Serone, A.P. / Suekawa-Pirrone, K. / Yang, Z.Y. / Zipfel, S.M. / Taylor, J.G.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionFeb 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 28, 2025Provider: 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)69,3025
Polymers68,4312
Non-polymers8713
Water3,135174
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6903
Polymers34,2161
Non-polymers4752
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)34,6122
Polymers34,2161
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.980, 117.570, 140.320
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
Components on special symmetry positions
IDModelComponents
11A-674-

HOH

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Components

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


Mass: 34215.516 Da / Num. of mol.: 2 / Fragment: kinase domain
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-A1BW0 / (6P)-6-[(8R)-3-cyanopyrrolo[1,2-b]pyridazin-7-yl]-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-4-(methylamino)pyridine-3-carboxamide


Mass: 396.418 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H21FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.71 Å3/Da / Density % sol: 54.64 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 2.15 M ammonium sulfate, 100 mM Hepes-NaOH at pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 5, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.99→46.44 Å / Num. obs: 97588 / % possible obs: 99.24 % / Redundancy: 3.4 % / CC1/2: 0.997 / Net I/σ(I): 7.24
Reflection shellResolution: 1.99→2.02 Å / Num. unique obs: 3387 / CC1/2: 0.28

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→46.44 Å / SU ML: 0.3158 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.0129
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2458 3829 3.93 %
Rwork0.2046 93562 -
obs0.2062 97391 99.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.94 Å2
Refinement stepCycle: LAST / Resolution: 1.99→46.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4576 0 62 174 4812
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01174716
X-RAY DIFFRACTIONf_angle_d1.156376
X-RAY DIFFRACTIONf_chiral_restr0.0671711
X-RAY DIFFRACTIONf_plane_restr0.0115814
X-RAY DIFFRACTIONf_dihedral_angle_d16.4381743
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.99-2.020.37841290.37153156X-RAY DIFFRACTION91.84
2.02-2.050.34681440.34563514X-RAY DIFFRACTION99.03
2.05-2.070.37691420.3393440X-RAY DIFFRACTION99.06
2.07-2.10.34051430.32753457X-RAY DIFFRACTION99.59
2.1-2.130.31791410.30883495X-RAY DIFFRACTION99.51
2.13-2.170.36861390.30683497X-RAY DIFFRACTION99.43
2.17-2.20.28281390.33425X-RAY DIFFRACTION99.53
2.2-2.240.29341430.27813436X-RAY DIFFRACTION99.03
2.24-2.280.34521430.29343500X-RAY DIFFRACTION99.7
2.28-2.330.27971460.25983495X-RAY DIFFRACTION99.81
2.33-2.370.29321430.2543541X-RAY DIFFRACTION99.81
2.37-2.420.33711460.2443455X-RAY DIFFRACTION99.78
2.43-2.480.28891380.23163471X-RAY DIFFRACTION99.86
2.48-2.540.27761410.22883508X-RAY DIFFRACTION99.81
2.54-2.610.23791450.22483473X-RAY DIFFRACTION99.83
2.61-2.690.26341410.223473X-RAY DIFFRACTION99.78
2.69-2.780.24051460.21743472X-RAY DIFFRACTION99.7
2.78-2.870.28521430.22023468X-RAY DIFFRACTION99.64
2.87-2.990.27331420.20313515X-RAY DIFFRACTION99.56
2.99-3.130.24631410.20823420X-RAY DIFFRACTION99.39
3.13-3.290.23791450.19843499X-RAY DIFFRACTION99.13
3.29-3.50.25861400.19473463X-RAY DIFFRACTION99.72
3.5-3.770.23611410.17023520X-RAY DIFFRACTION99.67
3.77-4.150.18321360.16253463X-RAY DIFFRACTION99.45
4.15-4.740.19921470.14973469X-RAY DIFFRACTION99.59
4.75-5.970.18721470.18543477X-RAY DIFFRACTION99.18
5.98-46.440.24771380.1773460X-RAY DIFFRACTION99.12

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