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- PDB-8atb: Discovery of IRAK4 Inhibitor 16 -

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Basic information

Entry
Database: PDB / ID: 8atb
TitleDiscovery of IRAK4 Inhibitor 16
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-O0H / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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 22, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 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 1.2Feb 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)67,7105
Polymers66,6372
Non-polymers1,0733
Water1,69394
1
AAA: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author
  • Evidence: MONOMERIC
  • 33.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)33,9013
Polymers33,3191
Non-polymers5832
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)33,8092
Polymers33,3191
Non-polymers4901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.200, 117.500, 136.600
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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


Mass: 33318.582 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-O0H / ~{N}-[6-ethoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxidanylidene-ethyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide


Mass: 490.478 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H25F3N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.64 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.9
Details: 0.1M sodium acetate buffer, 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: Jul 11, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.34→48.95 Å / Num. obs: 178315 / % possible obs: 99.8 % / Redundancy: 5.9 % / CC1/2: 0.999 / Rrim(I) all: 0.095 / Net I/σ(I): 16.25
Reflection shellResolution: 2.34→2.48 Å / Num. unique obs: 4796 / CC1/2: 0.805 / Rrim(I) all: 0.83 / % possible all: 99.6

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Processing

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

Resolution: 2.35→48.893 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.908 / SU B: 18.145 / SU ML: 0.206 / Cross valid method: FREE R-VALUE / ESU R: 0.336 / ESU R Free: 0.247
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2601 888 3 %
Rwork0.2123 28708 -
all0.214 --
obs-29596 99.865 %
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: 55.616 Å2
Baniso -1Baniso -2Baniso -3
1--1.049 Å2-0 Å2-0 Å2
2--2.564 Å20 Å2
3----1.516 Å2
Refinement stepCycle: LAST / Resolution: 2.35→48.893 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4416 0 76 94 4586
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0134579
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174329
X-RAY DIFFRACTIONr_angle_refined_deg1.1571.6396188
X-RAY DIFFRACTIONr_angle_other_deg1.0521.58310000
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4495557
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.69524.009227
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.80915805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3181518
X-RAY DIFFRACTIONr_chiral_restr0.0360.2598
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025107
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02969
X-RAY DIFFRACTIONr_nbd_refined0.1640.2899
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1610.24109
X-RAY DIFFRACTIONr_nbtor_refined0.1480.22222
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22101
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1050.2128
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1050.29
X-RAY DIFFRACTIONr_nbd_other0.1540.284
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.110.27
X-RAY DIFFRACTIONr_mcbond_it2.1874.0832245
X-RAY DIFFRACTIONr_mcbond_other2.1864.0812244
X-RAY DIFFRACTIONr_mcangle_it3.8139.1582797
X-RAY DIFFRACTIONr_mcangle_other3.8139.1622798
X-RAY DIFFRACTIONr_scbond_it2.3794.442333
X-RAY DIFFRACTIONr_scbond_other2.3794.4412334
X-RAY DIFFRACTIONr_scangle_it4.1889.7973391
X-RAY DIFFRACTIONr_scangle_other4.1879.7993392
X-RAY DIFFRACTIONr_lrange_it7.10549.0894946
X-RAY DIFFRACTIONr_lrange_other7.09549.0674934
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
2.35-2.4110.3650.29120990.29121640.7840.8011000.257
2.411-2.4770.317630.27420450.27521090.8280.85199.95260.24
2.477-2.5480.246610.26419800.26420410.8810.8661000.232
2.548-2.6270.276600.27119450.27220060.8490.85399.95010.239
2.627-2.7130.32580.24118670.24419250.8490.8821000.213
2.713-2.8070.255560.24418030.24518590.8970.8891000.212
2.807-2.9130.312540.2317610.23318150.8830.9021000.203
2.913-3.0320.246520.22816830.22917360.9180.91199.94240.199
3.032-3.1660.269500.20916060.21116580.8770.92399.87940.186
3.166-3.320.238480.21515690.21616180.9150.92399.93820.191
3.32-3.4980.304460.2114700.21315160.8930.9221000.19
3.498-3.7090.243430.18914100.1914540.9050.94499.93120.174
3.709-3.9640.247420.17613310.17813740.9210.95299.92720.162
3.964-4.2790.177370.15912240.15912610.9590.9631000.15
4.279-4.6840.24360.16511370.16711760.940.96499.74490.16
4.684-5.2310.303320.19210570.19410890.9270.9531000.185
5.231-6.0280.276290.2269100.2279410.9160.92699.78750.214
6.028-7.3550.312240.2328030.2358300.9040.91699.63850.222
7.355-10.2860.213200.2026240.2036500.9450.9599.07690.208
10.286-48.8930.234120.2543840.2534090.9340.9496.82150.278
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.48320.5782-0.21311.1765-0.80431.38250.1639-0.15580.19140.1249-0.1486-0.02480.03910.1963-0.01530.0375-0.0127-0.0070.1727-0.02430.045728.41731.26413.854
22.7545-0.16430.04890.3642-0.21722.10790.05780.2793-0.11230.07180.0072-0.00430.21850.0867-0.0650.0935-0.00350.02420.1471-0.02510.045110.80125.226-16.037
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLAAA165 - 459
2X-RAY DIFFRACTION2ALLBBB165 - 459

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