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- PDB-8br6: Discovery of IRAK4 Inhibitor 40 -

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Basic information

Entry
Database: PDB / ID: 8br6
TitleDiscovery of IRAK4 Inhibitor 40
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / IRAK4 / KINASE
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
ACETATE ION / Chem-R6I / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.167 Å
AuthorsSchafer, M. / Bothe, U. / Schmidt, N. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Boemer, U. / Peters, M. / Denner, K. ...Schafer, M. / Bothe, U. / Schmidt, N. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Boemer, U. / Peters, M. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wengner, A.M. / Guimond, N. / Thaler, T. / Platzek, J. / Ewerspaecher, U. / Steuber, H. / Steinmeyer, A. / Zollner, T.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 .
Authors: Bothe, U. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Bomer, U. / Peters, M. / Rausch, A. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wengner, A.M. ...Authors: Bothe, U. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Bomer, U. / Peters, M. / Rausch, A. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wengner, A.M. / Guimond, N. / Thaler, T. / Platzek, J. / Eberspacher, U. / Schafer, M. / Steuber, H. / Zollner, T.M. / Steinmeyer, A. / Schmidt, N.
History
DepositionNov 22, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Interleukin-1 receptor-associated kinase 4
BBB: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,5015
Polymers66,5732
Non-polymers9283
Water1,910106
1
AAA: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author
  • 33.7 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)33,7212
Polymers33,2871
Non-polymers4351
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author
  • 33.8 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)33,7803
Polymers33,2871
Non-polymers4942
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.725, 118.573, 138.709
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11AAA-1112-

HOH

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Components

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


Mass: 33286.582 Da / Num. of mol.: 2 / Mutation: K400A, E401A, E402A
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-R6I / ~{N}-[6-methoxy-2-(2-methylsulfonylethyl)-1,3-dihydroindazol-5-yl]-6-(2-oxidanylpropan-2-yl)pyridine-2-carboxamide


Mass: 434.509 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H26N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.72 Å3/Da / Density % sol: 54.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M sodium acetate buffer pH 4.9, 2.13-2.145M sodium malonate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 11, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.167→46.303 Å / Num. obs: 38659 / % possible obs: 99.7 % / Redundancy: 5.01 % / CC1/2: 0.998 / Rrim(I) all: 0.138 / Net I/σ(I): 10.85
Reflection shellResolution: 2.17→2.3 Å / Mean I/σ(I) obs: 1.71 / Num. unique obs: 6104 / CC1/2: 0.651

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house model

Resolution: 2.167→46.303 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.932 / WRfactor Rfree: 0.227 / WRfactor Rwork: 0.191 / SU B: 8.099 / SU ML: 0.187 / Average fsc free: 0.8409 / Average fsc work: 0.8539 / Cross valid method: THROUGHOUT / ESU R: 0.237 / ESU R Free: 0.197
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2513 1932 5.001 %
Rwork0.2133 36701 -
all0.215 --
obs-38633 99.634 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 48.702 Å2
Baniso -1Baniso -2Baniso -3
1--0.289 Å2-0 Å2-0 Å2
2--2.981 Å20 Å2
3----2.692 Å2
Refinement stepCycle: LAST / Resolution: 2.167→46.303 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4440 0 64 106 4610
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0134594
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164364
X-RAY DIFFRACTIONr_angle_refined_deg1.221.6576216
X-RAY DIFFRACTIONr_angle_other_deg1.1071.59110025
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0095564
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.54824.133225
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.79615818
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3571518
X-RAY DIFFRACTIONr_chiral_restr0.0430.2604
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025136
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02964
X-RAY DIFFRACTIONr_nbd_refined0.1710.2902
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1670.24097
X-RAY DIFFRACTIONr_nbtor_refined0.1510.22206
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22098
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2140
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1670.29
X-RAY DIFFRACTIONr_nbd_other0.1720.280
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1630.27
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0140.21
X-RAY DIFFRACTIONr_mcbond_it3.5773.3142263
X-RAY DIFFRACTIONr_mcbond_other3.5763.3132261
X-RAY DIFFRACTIONr_mcangle_it5.7711.1542818
X-RAY DIFFRACTIONr_mcangle_other5.76911.1562819
X-RAY DIFFRACTIONr_scbond_it4.2513.6152330
X-RAY DIFFRACTIONr_scbond_other4.253.6162331
X-RAY DIFFRACTIONr_scangle_it7.2911.9313395
X-RAY DIFFRACTIONr_scangle_other7.28911.9313396
X-RAY DIFFRACTIONr_lrange_it9.35160.24992
X-RAY DIFFRACTIONr_lrange_other9.35660.2164981
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.167-2.2230.3461370.35426010.35328280.5810.57396.81750.337
2.223-2.2840.371370.3326080.33227470.6590.67499.92720.305
2.284-2.350.3821350.30925710.31227110.7520.76399.81560.282
2.35-2.4220.3221300.2824610.28225930.7710.80799.92290.249
2.422-2.5010.3151250.26823850.27125140.8340.83499.84090.23
2.501-2.5890.2571240.27123380.2724670.8650.85499.79730.233
2.589-2.6860.2951170.25322250.25523440.8570.87699.91470.223
2.686-2.7960.3091140.24821690.25122840.8420.87499.95620.217
2.796-2.9190.3121090.24220690.24521780.8530.8961000.21
2.919-3.0610.2721050.23520050.23621130.9050.91599.8580.208
3.061-3.2260.294990.22818860.23119860.890.91899.94960.207
3.226-3.4210.223960.21718070.21819060.9350.93599.84260.201
3.421-3.6550.223890.1916970.19117870.9460.95399.9440.18
3.655-3.9460.173830.16215810.16216640.9610.9651000.154
3.946-4.320.182770.14214700.14415490.9630.9799.87090.139
4.32-4.8240.202710.15313310.15614060.9560.97199.71550.152
4.824-5.5610.267620.1911780.19412410.940.95199.91940.188
5.561-6.7860.289530.21110260.21410790.9170.9461000.206
6.786-9.4960.2420.1647980.1658420.9530.96899.76250.168
9.496-46.3030.175270.2094950.2075300.9750.96698.49060.246

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