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- PDB-8tvm: IRAK4 in complex with compound 24 -

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Basic information

Entry
Database: PDB / ID: 8tvm
TitleIRAK4 in complex with compound 24
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 / cytosol / cytoplasm
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: 2.1 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 1.1Nov 6, 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

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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
Water4,954275
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)136.380, 141.980, 87.780
Angle α, β, γ (deg.)90.000, 126.370, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,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-VDC / N-{1-[(1R,2R)-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.: 275 / 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: 2.6 Å3/Da / Density % sol: 52.69 %
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: 2.1→50 Å / Num. obs: 145187 / % possible obs: 93.3 % / Redundancy: 1.86 % / Biso Wilson estimate: 45.74 Å2 / CC1/2: 0.998 / Net I/σ(I): 9.12
Reflection shellResolution: 2.1→2.23 Å / Num. unique obs: 23404 / CC1/2: 0.588

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→48.52 Å / SU ML: 0.295 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.9701
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2465 3821 5 %
Rwork0.2212 72618 -
obs0.2225 76439 97.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.98 Å2
Refinement stepCycle: LAST / Resolution: 2.1→48.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8831 0 136 275 9242
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00439166
X-RAY DIFFRACTIONf_angle_d0.875612433
X-RAY DIFFRACTIONf_chiral_restr0.05351401
X-RAY DIFFRACTIONf_plane_restr0.00551579
X-RAY DIFFRACTIONf_dihedral_angle_d18.27973468
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.130.42081390.40012649X-RAY DIFFRACTION97.18
2.13-2.150.37671410.37122675X-RAY DIFFRACTION97.04
2.15-2.180.33751390.33272669X-RAY DIFFRACTION97.47
2.18-2.220.31691400.30762674X-RAY DIFFRACTION97.4
2.22-2.250.32891430.30742694X-RAY DIFFRACTION97.16
2.25-2.280.31341410.29862675X-RAY DIFFRACTION97.71
2.28-2.320.29521380.28212650X-RAY DIFFRACTION97.18
2.32-2.360.29491420.28142688X-RAY DIFFRACTION98.06
2.36-2.40.30551420.26872699X-RAY DIFFRACTION97.8
2.4-2.450.28351420.25692694X-RAY DIFFRACTION97.96
2.45-2.50.28491420.25982691X-RAY DIFFRACTION97.96
2.5-2.550.29981390.26642651X-RAY DIFFRACTION97.96
2.55-2.610.30061440.2592716X-RAY DIFFRACTION98.08
2.61-2.680.30791430.27312717X-RAY DIFFRACTION97.95
2.68-2.750.2561420.26742711X-RAY DIFFRACTION98.24
2.75-2.830.30641420.26082693X-RAY DIFFRACTION98.4
2.83-2.920.30021410.24552673X-RAY DIFFRACTION98.05
2.92-3.030.26851410.24972693X-RAY DIFFRACTION97.79
3.03-3.150.28021440.23462726X-RAY DIFFRACTION98.09
3.15-3.290.26841410.24292677X-RAY DIFFRACTION98.29
3.29-3.470.28631420.22672722X-RAY DIFFRACTION98.39
3.47-3.680.21841430.20632704X-RAY DIFFRACTION98.14
3.68-3.970.21721410.19362689X-RAY DIFFRACTION97.52
3.97-4.370.20111420.16782694X-RAY DIFFRACTION97.39
4.37-50.17821420.1732689X-RAY DIFFRACTION97.12
5-6.30.22821410.20762684X-RAY DIFFRACTION96.61
6.3-48.520.20961440.18682721X-RAY DIFFRACTION96.59

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