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- PDB-6uya: Crystal structure of Compound 19 bound to IRAK4 -

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Basic information

Entry
Database: PDB / ID: 6uya
TitleCrystal structure of Compound 19 bound to IRAK4
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsSIGNALING PROTEIN/INHIBITOR / kinase / inflammation / lupus / immunology / inhibitor / cancer / SIGNALING PROTEIN / SIGNALING PROTEIN-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 / 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-QL7 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsKiefer, J.R. / Bryan, M.C. / Lupardus, P.J. / Zarrin, A.A. / Rajapaksa, N.S. / Gobbi, A. / Drobnick, J. / Kolesnikov, A. / Liang, J. / Do, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity.
Authors: Rajapaksa, N.S. / Gobbi, A. / Drobnick, J. / Do, S. / Kolesnikov, A. / Liang, J. / Chen, Y. / Sujatha-Bhaskar, S. / Huang, Z. / Brightbill, H. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. ...Authors: Rajapaksa, N.S. / Gobbi, A. / Drobnick, J. / Do, S. / Kolesnikov, A. / Liang, J. / Chen, Y. / Sujatha-Bhaskar, S. / Huang, Z. / Brightbill, H. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. / Ran, Y. / An, L. / Emson, C. / Maher, J. / Wai, J. / McKenzie, B.S. / Lupardus, P.J. / Zarrin, A.A. / Kiefer, J.R. / Bryan, M.C.
History
DepositionNov 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)146,7089
Polymers144,6824
Non-polymers2,0265
Water15,979887
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5650 Å2
ΔGint-35 kcal/mol
Surface area48920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)140.882, 140.175, 87.559
Angle α, β, γ (deg.)90.000, 123.200, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-746-

HOH

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Components

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


Mass: 36170.531 Da / Num. of mol.: 4
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-QL7 / N-{2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-(morpholin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 482.507 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H27FN6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 887 / 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: 2.5 Å3/Da / Density % sol: 50.8 %
Crystal growTemperature: 292 K / Method: vapor diffusion
Details: 2.3M-2.7M ammonium sulfate, 0.1M HEPES Na pH 7.0-7.3

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.74→74.05 Å / Num. obs: 145142 / % possible obs: 99.7 % / Redundancy: 4.4 % / Biso Wilson estimate: 27.38 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.034 / Rrim(I) all: 0.072 / Net I/σ(I): 13.8 / Num. measured all: 632841
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.74-1.834.30.62891098212120.7520.3470.722.4100
5.5-74.054.20.0391972646450.9980.0210.04533.499.1

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Processing

Software
NameVersionClassification
Aimless0.2.8data scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NA

Resolution: 1.74→25.48 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.945 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.1 / SU Rfree Blow DPI: 0.096 / SU Rfree Cruickshank DPI: 0.095
RfactorNum. reflection% reflectionSelection details
Rfree0.207 7278 5.03 %RANDOM
Rwork0.181 ---
obs0.182 144614 99.7 %-
Displacement parametersBiso max: 120.02 Å2 / Biso mean: 32.37 Å2 / Biso min: 12.44 Å2
Baniso -1Baniso -2Baniso -3
1--2.5421 Å20 Å2-1.5177 Å2
2--3.2887 Å20 Å2
3----0.7466 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.74→25.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9042 0 145 887 10074
Biso mean--21.16 40.02 -
Num. residues----1147
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3354SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes272HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1425HARMONIC5
X-RAY DIFFRACTIONt_it9385HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
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_contact11789SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9385HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12712HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion16.83
LS refinement shellResolution: 1.74→1.78 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.256 554 5.18 %
Rwork0.209 10134 -
all0.211 10688 -
obs--99.98 %

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