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- PDB-8br7: Discovery of IRAK4 Inhibitors BAY1834845 and BAY1830839 -

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Basic information

Entry
Database: PDB / ID: 8br7
TitleDiscovery of IRAK4 Inhibitors BAY1834845 and BAY1830839
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
Chem-R6R / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.119 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. / Wenger, A.M. / Guimond, N. / Thaler, T. / Platzek, J. / Eberspaecher, 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)67,5984
Polymers66,5732
Non-polymers1,0252
Water73941
1
AAA: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author
  • 33.8 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)33,7992
Polymers33,2871
Non-polymers5131
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)33,7992
Polymers33,2871
Non-polymers5131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.258, 117.970, 139.861
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
11BBB-619-

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-R6R / 3-nitro-~{N}-[2-[2-oxidanylidene-2-[4-(phenylcarbonyl)piperazin-1-yl]ethyl]indazol-5-yl]benzamide


Mass: 512.517 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H24N6O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.7 Å3/Da / Density % sol: 54.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M sodium acetate buffer at pH 4.9, 1.5-1.7M ammonium citrate and 0.02M hexaaminecobalt(III)chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.119→19.77 Å / Num. obs: 35635 / % possible obs: 86.2 % / Redundancy: 6.49 % / CC1/2: 0.999 / Rrim(I) all: 0.115 / Net I/σ(I): 16.69
Reflection shellResolution: 2.12→2.25 Å / Mean I/σ(I) obs: 1.66 / Num. unique obs: 5751 / CC1/2: 0.701

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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: 2.119→19.768 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / WRfactor Rfree: 0.272 / WRfactor Rwork: 0.219 / SU B: 10.535 / SU ML: 0.245 / Average fsc free: 0.7544 / Average fsc work: 0.7705 / Cross valid method: THROUGHOUT / ESU R: 0.285 / ESU R Free: 0.237
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2879 1782 5.001 %
Rwork0.2387 33851 -
all0.241 --
obs-35633 86.176 %
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: 60.235 Å2
Baniso -1Baniso -2Baniso -3
1--1.059 Å2-0 Å2-0 Å2
2--4.994 Å20 Å2
3----3.935 Å2
Refinement stepCycle: LAST / Resolution: 2.119→19.768 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4344 0 76 41 4461
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0134498
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164264
X-RAY DIFFRACTIONr_angle_refined_deg1.2391.6636075
X-RAY DIFFRACTIONr_angle_other_deg1.111.5939790
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9935542
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.30324.072221
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.97215801
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5931518
X-RAY DIFFRACTIONr_chiral_restr0.0440.2585
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025015
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02937
X-RAY DIFFRACTIONr_nbd_refined0.1850.2994
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1770.24295
X-RAY DIFFRACTIONr_nbtor_refined0.1560.22197
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0740.22048
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1340.2125
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0250.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2390.225
X-RAY DIFFRACTIONr_nbd_other0.2210.2100
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.260.27
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1050.22
X-RAY DIFFRACTIONr_mcbond_it7.2696.0512195
X-RAY DIFFRACTIONr_mcbond_other7.2676.0512194
X-RAY DIFFRACTIONr_mcangle_it9.91413.5812728
X-RAY DIFFRACTIONr_mcangle_other9.91313.5822729
X-RAY DIFFRACTIONr_scbond_it8.0166.7452303
X-RAY DIFFRACTIONr_scbond_other7.9996.7442300
X-RAY DIFFRACTIONr_scangle_it11.66614.7623347
X-RAY DIFFRACTIONr_scangle_other11.63914.7613343
X-RAY DIFFRACTIONr_lrange_it14.2475.6434990
X-RAY DIFFRACTIONr_lrange_other14.25575.6584988
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
2.119-2.1730.3961470.40328010.40329830.3070.34398.82670.375
2.173-2.2320.3971400.40226620.40229140.3950.37796.15650.369
2.232-2.2960.412110.4971940.49328470.4470.4457.20060.475
2.296-2.3660.3671380.34126220.34327600.6580.6471000.301
2.366-2.4420.3161320.29525220.29626540.7410.7671000.257
2.442-2.5260.3541300.30824600.3125940.7370.76799.84580.264
2.526-2.620.3041250.26623850.26825120.8460.8599.92040.228
2.62-2.7250.334510.3279530.32724150.8510.82341.57350.267
2.725-2.8440.3691150.26321990.26823140.8180.8661000.229
2.844-2.980.2771120.23321250.23622370.8890.9041000.204
2.98-3.1370.3091050.23120000.23621050.8710.9021000.206
3.137-3.3220.3031010.2519200.25320210.8550.8871000.228
3.322-3.5440.37660.25612460.26218990.8380.88269.0890.226
3.544-3.8180.342650.26612300.26917830.8680.89172.63040.234
3.818-4.1670.238640.22312200.22416480.9260.92177.91260.196
4.167-4.6330.221750.17414350.17615100.9420.9561000.183
4.633-5.3010.207670.17912710.18113380.9510.9531000.187
5.301-6.3790.323590.21811190.22311780.9140.9391000.232
6.379-8.5850.245470.2038850.2059320.9410.9471000.225
8.585-19.7680.23320.1936020.1956380.9480.96199.3730.242

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