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- PDB-8atl: Discovery of IRAK4 Inhibitor 23 -

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Basic information

Entry
Database: PDB / ID: 8atl
TitleDiscovery of IRAK4 Inhibitor 23
Components(Interleukin-1 receptor-associated kinase 4) x 2
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-O6X / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.464 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
DepositionAug 23, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.2Jan 31, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Feb 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)67,5764
Polymers66,5892
Non-polymers9872
Water1,26170
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)33,7962
Polymers33,3031
Non-polymers4931
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)33,7802
Polymers33,2871
Non-polymers4931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.864, 118.789, 138.136
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-1115-

HOH

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Components

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


Mass: 33302.582 Da / Num. of mol.: 1 / 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: Protein Interleukin-1 receptor-associated kinase 4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 33286.582 Da / Num. of mol.: 1
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
#3: Chemical ChemComp-O6X / ~{N}-[6-methoxy-2-(2-morpholin-4-yl-2-oxidanylidene-ethyl)indazol-5-yl]-6-[(1~{R})-2,2,2-tris(fluoranyl)-1-oxidanyl-ethyl]pyridine-2-carboxamide


Mass: 493.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22F3N5O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 2.82 Å3/Da / Density % sol: 56.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.9
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: Nov 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.46→46.354 Å / Num. obs: 146185 / % possible obs: 99.8 % / Redundancy: 5.5 % / CC1/2: 0.999 / Rrim(I) all: 0.074 / Net I/σ(I): 17.3
Reflection shellResolution: 2.46→2.6 Å / Num. unique obs: 4006 / CC1/2: 0.926 / Rrim(I) all: 0.491 / % possible all: 100

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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: 2.464→46.354 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.92 / SU B: 8.804 / SU ML: 0.196 / Cross valid method: FREE R-VALUE / ESU R: 0.403 / ESU R Free: 0.259
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2429 1316 5.001 %
Rwork0.1988 25000 -
all0.201 --
obs-26316 99.392 %
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: 56.279 Å2
Baniso -1Baniso -2Baniso -3
1--0.337 Å2-0 Å2-0 Å2
2--3.653 Å20 Å2
3----3.316 Å2
Refinement stepCycle: LAST / Resolution: 2.464→46.354 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4354 0 70 70 4494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0134526
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174295
X-RAY DIFFRACTIONr_angle_refined_deg1.2741.6626117
X-RAY DIFFRACTIONr_angle_other_deg1.0911.5989922
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6995549
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.82723.929224
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.60715807
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.041519
X-RAY DIFFRACTIONr_chiral_restr0.0410.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025033
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02959
X-RAY DIFFRACTIONr_nbd_refined0.1680.2811
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1680.23878
X-RAY DIFFRACTIONr_nbtor_refined0.150.22148
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.22112
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1070.2106
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1120.212
X-RAY DIFFRACTIONr_nbd_other0.1620.281
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.220.26
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1030.21
X-RAY DIFFRACTIONr_mcbond_it5.2915.692211
X-RAY DIFFRACTIONr_mcbond_other5.2895.6882210
X-RAY DIFFRACTIONr_mcangle_it8.07512.7472749
X-RAY DIFFRACTIONr_mcangle_other8.07412.7512750
X-RAY DIFFRACTIONr_scbond_it6.1236.3042314
X-RAY DIFFRACTIONr_scbond_other6.1246.3052310
X-RAY DIFFRACTIONr_scangle_it9.52213.8073366
X-RAY DIFFRACTIONr_scangle_other9.52313.8083363
X-RAY DIFFRACTIONr_lrange_it11.90667.5554779
X-RAY DIFFRACTIONr_lrange_other11.90867.5594770
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
2.464-2.5280.304910.30917350.30819220.8460.83595.00520.287
2.528-2.5970.318930.28417740.28618690.820.84699.8930.264
2.597-2.6720.316910.2717260.27318170.850.8761000.245
2.672-2.7540.247890.23516820.23517730.8770.89799.88720.209
2.754-2.8440.27860.22516380.22717270.8950.91599.82630.2
2.844-2.9440.257840.21315930.21516780.9140.92199.94040.186
2.944-3.0540.229810.21415370.21416200.9110.92699.87650.189
3.054-3.1780.261770.21314580.21515380.910.92699.80490.191
3.178-3.3190.289740.21414180.21714940.8980.92899.86610.197
3.319-3.480.228720.20313700.20414440.9310.94399.86150.189
3.48-3.6670.235680.18312940.18613630.9320.95499.92660.173
3.667-3.8880.213650.18312360.18413030.9450.95199.84650.172
3.888-4.1550.194610.15911490.16112120.9510.96199.8350.153
4.155-4.4850.204570.1510760.15311350.9590.96499.82380.146
4.485-4.9080.219520.1610030.16310580.9480.96199.71640.16
4.908-5.480.238480.1919080.1949640.9280.94799.17010.188
5.48-6.3130.268430.2038210.2078690.9280.93899.42460.202
6.313-7.6960.236370.2046920.2067320.9260.94499.59020.204
7.696-10.7360.224290.1755470.1785840.9520.96398.63010.199
10.736-46.3540.341180.2443430.2483690.910.94397.8320.291

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