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- PDB-8tvn: IRAK4 in complex with compound 23 -

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Basic information

Entry
Database: PDB / ID: 8tvn
TitleIRAK4 in complex with compound 23
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/INHIBITOR / kinase / TRANSFERASE / 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 / interleukin-1 receptor binding / neutrophil mediated immunity ...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 / interleukin-1 receptor binding / neutrophil mediated immunity / interleukin-1-mediated signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / extrinsic component of plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / JNK cascade / positive regulation of smooth muscle cell proliferation / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / lipopolysaccharide-mediated signaling pathway / Interleukin-1 signaling / cytokine-mediated signaling pathway / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of canonical NF-kappaB signal transduction / 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 / magnesium ion binding / cell surface / 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 / 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: 1.95 Å
AuthorsMetrick, C.M. / Chodaparambil, J.V.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.
Authors: Bolduc, P.N. / Pfaffenbach, M. / Evans, R. / Xin, Z. / Henry, K.L. / Gao, F. / Fang, T. / Silbereis, J. / Vera Rebollar, J. / Li, P. / Chodaparambil, J.V. / Metrick, C. / Peterson, E.A.
History
DepositionAug 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
C: Interleukin-1 receptor-associated kinase 4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,5028
Polymers138,6324
Non-polymers1,8704
Water8,017445
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1252
Polymers34,6581
Non-polymers4671
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)35,1252
Polymers34,6581
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1252
Polymers34,6581
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1252
Polymers34,6581
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.920, 94.180, 98.920
Angle α, β, γ (deg.)90.000, 108.470, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 34657.938 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-VE9 / N-{1-[(1R,2S)-2-fluorocyclopropyl]-2-oxo-1,2-dihydropyridin-3-yl}-2-[(1R,4r)-1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl]-6-[(propan-2-yl)oxy]-2H-pyrazolo[3,4-b]pyridine-5-carboxamide


Mass: 467.493 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H26FN5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 445 / 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: 2.39 Å3/Da / Density % sol: 48.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: Sodium Malonate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 1M / Detector: PIXEL / Date: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 180277 / % possible obs: 96.3 % / Redundancy: 1.81 % / Biso Wilson estimate: 42.23 Å2 / CC1/2: 0.999 / Net I/σ(I): 10.58
Reflection shellResolution: 1.95→2.07 Å / Num. unique obs: 29255 / CC1/2: 0.558

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→47.09 Å / SU ML: 0.2696 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.6303
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2425 4730 5 %
Rwork0.2061 89908 -
obs0.2079 94638 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.9 Å2
Refinement stepCycle: LAST / Resolution: 1.95→47.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8838 0 136 445 9419
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01399154
X-RAY DIFFRACTIONf_angle_d1.422212419
X-RAY DIFFRACTIONf_chiral_restr0.09311406
X-RAY DIFFRACTIONf_plane_restr0.01071577
X-RAY DIFFRACTIONf_dihedral_angle_d17.79693458
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.970.33761590.32653031X-RAY DIFFRACTION99.72
1.97-20.35771550.32352943X-RAY DIFFRACTION99.97
2-2.020.35461570.2932980X-RAY DIFFRACTION99.87
2.02-2.050.28761590.27033016X-RAY DIFFRACTION99.94
2.05-2.070.2971570.26032977X-RAY DIFFRACTION99.9
2.07-2.10.2581560.25512995X-RAY DIFFRACTION99.94
2.1-2.130.32711570.25382981X-RAY DIFFRACTION99.97
2.13-2.160.30381580.25242993X-RAY DIFFRACTION100
2.16-2.20.29181590.24843023X-RAY DIFFRACTION99.91
2.2-2.230.29751540.2382954X-RAY DIFFRACTION99.94
2.23-2.270.26211600.22763025X-RAY DIFFRACTION99.53
2.27-2.310.26091560.23172967X-RAY DIFFRACTION99.9
2.31-2.360.27011590.2313034X-RAY DIFFRACTION99.94
2.36-2.40.2781570.22692985X-RAY DIFFRACTION99.9
2.4-2.460.30881560.24052973X-RAY DIFFRACTION99.9
2.46-2.510.31161570.23742985X-RAY DIFFRACTION99.9
2.51-2.580.27821600.24323030X-RAY DIFFRACTION100
2.58-2.650.26251570.23832983X-RAY DIFFRACTION99.97
2.65-2.720.2591580.22483013X-RAY DIFFRACTION99.97
2.72-2.810.26381570.23422976X-RAY DIFFRACTION99.97
2.81-2.910.28111600.23293039X-RAY DIFFRACTION99.91
2.91-3.030.27941580.2313000X-RAY DIFFRACTION99.84
3.03-3.170.27861580.23093004X-RAY DIFFRACTION99.84
3.17-3.330.27081570.22022993X-RAY DIFFRACTION99.46
3.33-3.540.22681570.20122984X-RAY DIFFRACTION98.93
3.54-3.820.21131560.1912965X-RAY DIFFRACTION98.89
3.82-4.20.21391570.16692983X-RAY DIFFRACTION98.49
4.2-4.810.18561580.15552990X-RAY DIFFRACTION98.78
4.81-6.050.21111590.18883026X-RAY DIFFRACTION99.16
6.06-47.090.20731620.18073060X-RAY DIFFRACTION98.53

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