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- PDB-8w3x: Crystal structure of IRAK4 in complex with compound 6 -

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Basic information

Entry
Database: PDB / ID: 8w3x
TitleCrystal structure of IRAK4 in complex with compound 6
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4
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: 1.765 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 1.1Nov 13, 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)147,6538
Polymers146,3364
Non-polymers1,3174
Water13,115728
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9132
Polymers36,5841
Non-polymers3291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9132
Polymers36,5841
Non-polymers3291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9132
Polymers36,5841
Non-polymers3291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9132
Polymers36,5841
Non-polymers3291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.610, 140.110, 87.840
Angle α, β, γ (deg.)90.00, 124.67, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11D-657-

HOH

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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-A1AFH / 7-ethoxy-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide


Mass: 329.350 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H19N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 728 / 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: 2.47 Å3/Da / Density % sol: 50.12 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: AMMONIUM CITRATE

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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: 1.765→48.94 Å / Num. obs: 127742 / % possible obs: 95.1 % / Redundancy: 3.4 % / CC1/2: 0.999 / Net I/σ(I): 12.2
Reflection shellResolution: 1.765→1.8 Å / Num. unique obs: 4207 / CC1/2: 0.591

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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: 1.765→48.94 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.953 / SU R Cruickshank DPI: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.117 / SU Rfree Blow DPI: 0.107 / SU Rfree Cruickshank DPI: 0.107
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2124 6272 4.91 %RANDOM
Rwork0.1901 ---
obs0.1912 127742 92 %-
Displacement parametersBiso mean: 37.62 Å2
Baniso -1Baniso -2Baniso -3
1-0.9294 Å20 Å2-0.2999 Å2
2---0.4091 Å20 Å2
3----0.5203 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.765→48.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8975 0 224 728 9927
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0099441HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9712818HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3352SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1696HARMONIC5
X-RAY DIFFRACTIONt_it9365HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion15.98
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1225SEMIHARMONIC5
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_contact8370SEMIHARMONIC4
LS refinement shellResolution: 1.765→1.79 Å
RfactorNum. reflection% reflection
Rfree0.2822 115 4.5 %
Rwork0.2731 2440 -
obs--46.84 %
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)
10.8584-0.07710.04541.8604-0.37822.60340.04440.1940.0325-0.1799-0.0588-0.0972-0.1090.10540.0144-0.1810.02070.0138-0.1590.0193-0.211738.410714.641-5.8627
21.52850.0099-0.55191.6687-0.25581.5254-0.02870.0352-0.18570.1052-0.00430.14840.0192-0.25910.0329-0.2028-0.00260.0277-0.18660.0155-0.17844.9747-14.522239.6404
31.26380.1292-0.17421.25660.43610.9194-0.05370.0891-0.1547-0.02350.01-0.00310.11260.0060.0437-0.13450.03860.0163-0.1933-0.0143-0.181233.3917-16.16611.465
40.7338-0.2840.05151.0934-0.1791.12540.038-0.07250.03220.07990.0040.1001-0.1528-0.0544-0.042-0.15720.00670.0178-0.2161-0.0237-0.192119.723816.423229.8479
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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