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- PDB-8w3w: Crystal structure of IRAK4 in complex with compound 4 -

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Basic information

Entry
Database: PDB / ID: 8w3w
TitleCrystal structure of IRAK4 in complex with compound 4
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / Interleukin-1 receptor-associated kinase 4
Function / homology
Function and homology information


MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / 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 ...MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / 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 / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / extrinsic component of plasma membrane / toll-like receptor signaling pathway / 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 / 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 / cell surface / magnesium ion binding / 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: 1.976 Å
AuthorsHan, S. / Knafels, J.D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: In Retrospect: Root-Cause Analysis of Structure-Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833).
Authors: Wright, S.W. / Farley, K.A. / Han, S. / Knafels, J.D. / Lee, K.L.
History
DepositionFeb 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 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)147,5978
Polymers146,3364
Non-polymers1,2614
Water10,737596
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author&software
  • 36.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,8992
Polymers36,5841
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author&software
  • 36.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,8992
Polymers36,5841
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author&software
  • 36.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,8992
Polymers36,5841
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


  • defined by author&software
  • 36.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,8992
Polymers36,5841
Non-polymers3151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.720, 139.260, 88.040
Angle α, β, γ (deg.)90.00, 124.84, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 36584.020 Da / Num. of mol.: 4 / Fragment: UNP residues 154-460
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-A1AFO / 7-methoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide


Mass: 315.324 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H17N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 596 / 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: 2.45 Å3/Da / Density % sol: 49.87 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: ammonium citrate tribasic

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Data collection

DiffractionMean temperature: 173 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 3, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.976→47.09 Å / Num. obs: 93889 / % possible obs: 95.8 % / Redundancy: 3.5 % / CC1/2: 0.999 / Net I/σ(I): 15
Reflection shellResolution: 1.976→2.01 Å / Num. unique obs: 3963 / CC1/2: 0.508

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (22-FEB-2023)refinement
HKL-2000data reduction
HKL-2000data scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.976→47.09 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.951 / SU R Cruickshank DPI: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.164 / SU Rfree Blow DPI: 0.137 / SU Rfree Cruickshank DPI: 0.138
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2126 4785 5.1 %RANDOM
Rwork0.1921 ---
obs0.1932 93889 95.3 %-
Displacement parametersBiso mean: 44.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.1535 Å20 Å2-1.3725 Å2
2---0.4026 Å20 Å2
3---0.5561 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.976→47.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9054 0 220 596 9870
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089511HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9512907HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3384SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1704HARMONIC5
X-RAY DIFFRACTIONt_it9443HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion16.73
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1236SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8149SEMIHARMONIC4
LS refinement shellResolution: 1.98→1.99 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3056 -4.37 %
Rwork0.2757 1796 -
all0.2769 1878 -
obs--77 %
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)
11.1070.05820.22152.2414-0.14993.45040.02640.24430.056-0.2621-0.067-0.1121-0.15790.15140.0407-0.17680.02190.0028-0.15510.0208-0.187138.284914.5583-5.8996
21.8025-0.1641-0.56561.9127-0.33141.7399-0.01850.047-0.21210.1123-0.00270.1744-0.0241-0.2710.0211-0.1990.0030.0269-0.19760.016-0.18144.889-14.451439.5303
31.39210.029-0.24641.49180.58940.9989-0.07680.0666-0.14660.00750.0352-0.03050.13440.04540.0416-0.12140.0460.0036-0.1785-0.0075-0.175733.4756-16.099111.5821
40.9326-0.30310.00861.2461-0.19351.08950.0295-0.10.03290.1143-0.00240.1247-0.1512-0.0584-0.0271-0.14650.00690.0029-0.1863-0.023-0.166819.845416.352729.9018
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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