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- PDB-6vql: CRYSTAL STRUCTURE OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 (... -

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Basic information

Entry
Database: PDB / ID: 6vql
TitleCRYSTAL STRUCTURE OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 (IRAK4-WT) COMPLEX WITH A NICOTINAMIDE INHIBITOR
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / KINASE / TRANSFERASE / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-R7S / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.069 Å
AuthorsSack, J.S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.
Authors: Nair, S. / Kumar, S.R. / Paidi, V.R. / Sistla, R. / Kantheti, D. / Polimera, S.R. / Thangavel, S. / Mukherjee, A.J. / Das, M. / Bhide, R.S. / Pitts, W.J. / Murugesan, N. / Dudhgoankar, S. / ...Authors: Nair, S. / Kumar, S.R. / Paidi, V.R. / Sistla, R. / Kantheti, D. / Polimera, S.R. / Thangavel, S. / Mukherjee, A.J. / Das, M. / Bhide, R.S. / Pitts, W.J. / Murugesan, N. / Dudhgoankar, S. / Nagar, J. / Subramani, S. / Mazumder, D. / Carman, J.A. / Holloway, D.A. / Li, X. / Fereshteh, M.P. / Ruepp, S. / Palanisamy, K. / Mariappan, T.T. / Maddi, S. / Saxena, A. / Elzinga, P. / Chimalakonda, A. / Ruan, Q. / Ghosh, K. / Bose, S. / Sack, J. / Yan, C. / Kiefer, S.E. / Xie, D. / Newitt, J.A. / Saravanakumar, S.P. / Rampulla, R.A. / Barrish, J.C. / Carter, P.H. / Hynes Jr., J.
History
DepositionFeb 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 9, 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)139,76918
Polymers137,0904
Non-polymers2,67914
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6870 Å2
ΔGint-134 kcal/mol
Surface area47180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.352, 140.827, 86.068
Angle α, β, γ (deg.)90.000, 126.200, 90.000
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: 34272.566 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: unidentified baculovirus
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-R7S / 6-[(1,3-benzothiazol-6-yl)amino]-4-(cyclopropylamino)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide


Mass: 429.511 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C21H24FN5O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.41 Å3/Da / Density % sol: 49.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: NULL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.069→43.15 Å / Num. obs: 41320 / % possible obs: 52.2 % / Redundancy: 3.2 % / Biso Wilson estimate: 35.11 Å2 / Rmerge(I) obs: 0.071 / Net I/σ(I): 10.1
Reflection shellResolution: 2.069→2.33 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.466 / Num. unique obs: 4098 / % possible all: 8.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (3-OCT-2019)refinement
Aimlessdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5w85

5w85


Resolution: 2.069→43 Å / Cor.coef. Fo:Fc: 0.884 / Cor.coef. Fo:Fc free: 0.854 / SU R Cruickshank DPI: 0.791 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.673 / SU Rfree Blow DPI: 0.32 / SU Rfree Cruickshank DPI: 0.332
RfactorNum. reflection% reflectionSelection details
Rfree0.279 2101 5.08 %RANDOM
Rwork0.2417 ---
obs0.2436 41320 52.2 %-
Displacement parametersBiso max: 142.63 Å2 / Biso mean: 40.31 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--0.2955 Å20 Å20.68 Å2
2---0.3545 Å20 Å2
3---0.65 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 2.069→43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8738 0 170 52 8960
Biso mean--49.66 20.06 -
Num. residues----1149
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3064SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1624HARMONIC5
X-RAY DIFFRACTIONt_it9055HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1212SEMIHARMONIC5
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_contact7116SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9055HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg12300HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion18.46
LS refinement shellResolution: 2.07→2.33 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2556 45 5.44 %
Rwork0.2251 782 -
obs--5.43 %

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