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- PDB-6egd: Crystal structure of the unphosphorylated IRAK4 kinase domain Bou... -

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Basic information

Entry
Database: PDB / ID: 6egd
TitleCrystal structure of the unphosphorylated IRAK4 kinase domain Bound to a type I inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Unphosphorylated / Inactive / SIGNALING PROTEIN / 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 / 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 / Interleukin-1 signaling / cytokine-mediated signaling pathway / PIP3 activates AKT signaling / kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of canonical NF-kappaB signal transduction / cellular response to lipopolysaccharide / endosome membrane / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / innate immune response / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/Threonine protein kinases, catalytic domain ...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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-J87 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsFerrao, R. / Wu, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) United States
CitationJournal: J.Biol.Chem. / Year: 2019
Title: Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).
Authors: Wang, L. / Ferrao, R. / Li, Q. / Hatcher, J.M. / Choi, H.G. / Buhrlage, S.J. / Gray, N.S. / Wu, H.
History
DepositionAug 19, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _citation_author.identifier_ORCID
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: Interleukin-1 receptor-associated kinase 4
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,2264
Polymers67,4332
Non-polymers7932
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation, light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1390 Å2
ΔGint-0 kcal/mol
Surface area25000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.450, 59.500, 75.620
Angle α, β, γ (deg.)90.00, 111.81, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Interleukin-1 receptor-associated kinase 4 / IRAK4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 33716.324 Da / Num. of mol.: 2 / Fragment: Protein kinase domain residues 164-460
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-J87 / N-[2-methoxy-4-(morpholin-4-yl)phenyl]-2-(pyridin-3-yl)-1,3-thiazole-5-carboxamide


Mass: 396.463 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / Source method: isolated from a natural source / Formula: H2O

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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: 2.21 Å3/Da / Density % sol: 44.42 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / Details: 150 mM DL-Malic acid and 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 31, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.1→44.29 Å / Num. obs: 34388 / % possible obs: 99.29 % / Redundancy: 6.7 % / CC1/2: 1 / Rmerge(I) obs: 0.053 / Net I/σ(I): 21.17
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.93 / Mean I/σ(I) obs: 1.97 / Num. unique obs: 3358 / CC1/2: 0.77 / % possible all: 98.16

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→44.29 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.52
RfactorNum. reflection% reflection
Rfree0.2303 1995 5.8 %
Rwork0.1814 --
obs0.1843 34382 99.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→44.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4292 0 56 143 4491
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074426
X-RAY DIFFRACTIONf_angle_d1.0725962
X-RAY DIFFRACTIONf_dihedral_angle_d15.8531663
X-RAY DIFFRACTIONf_chiral_restr0.039659
X-RAY DIFFRACTIONf_plane_restr0.004768
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0999-2.15240.33541460.24642245X-RAY DIFFRACTION98
2.1524-2.21060.29131340.24082320X-RAY DIFFRACTION99
2.2106-2.27570.31161260.22742267X-RAY DIFFRACTION99
2.2757-2.34910.28441580.2152274X-RAY DIFFRACTION99
2.3491-2.43310.29681360.21052330X-RAY DIFFRACTION99
2.4331-2.53050.28021430.20822284X-RAY DIFFRACTION99
2.5305-2.64560.27881420.2042285X-RAY DIFFRACTION99
2.6456-2.78510.29851440.2012317X-RAY DIFFRACTION99
2.7851-2.95960.27171430.21222321X-RAY DIFFRACTION100
2.9596-3.1880.25441400.19652327X-RAY DIFFRACTION100
3.188-3.50870.22651470.18122321X-RAY DIFFRACTION100
3.5087-4.01620.23521420.16112344X-RAY DIFFRACTION100
4.0162-5.05880.16621460.14262353X-RAY DIFFRACTION100
5.0588-44.30330.19461480.17892399X-RAY DIFFRACTION99
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)
17.0104-1.5529-0.88811.41030.58961.14460.0360.1385-0.3711-0.3701-0.13610.17630.1328-0.02260.08560.4873-0.0142-0.08810.3321-0.00070.3671-14.0134-21.8627-5.1932
22.88170.8567-0.74884.8824-1.64123.43050.07040.2417-0.2907-0.2601-0.1633-0.03020.59620.11660.14250.44120.0282-0.00740.3881-0.01970.269-6.496-14.8909-9.2038
33.40370.8932-0.63593.957-0.55344.79-0.04690.29070.2846-0.28460.10030.19430.0047-0.0836-0.00940.29950.0169-0.0160.32260.02990.305-4.15632.7281-17.9742
46.37790.6497-1.0323.38280.24222.89670.25740.231-1.0517-0.0208-0.64670.5350.5865-0.43280.53220.4986-0.2099-0.03260.5991-0.10960.8068-4.8601-27.2076-63.7582
51.607-0.7906-1.13784.75851.71462.468-0.20490.038-0.73030.4962-0.49551.33460.3463-0.60870.52020.4564-0.16610.06070.5552-0.07270.8164-9.1772-17.324-58.3235
63.21591.86180.1645.04910.72662.8762-0.0948-0.0041-0.4158-0.0302-0.23120.44720.0661-0.30310.24980.3146-0.05880.06550.3545-0.06260.5181-0.5097-13.0175-61.4066
79.4872-1.177-3.39974.22360.35263.8230.24920.81860.2672-0.3697-0.02820.1995-0.4027-0.4599-0.19070.4952-0.0408-0.0170.40150.03030.3174-5.16733.0743-58.8318
82.7539-1.5484-0.19673.4205-0.39584.9741-0.0419-0.1682-0.3880.17650.17610.4125-0.3716-0.365-0.11480.3203-0.06290.03210.36910.02530.4043-7.3071-5.672-50.2156
92.1367-1.7907-0.70696.1347-1.09127.1356-0.309-0.4819-0.43070.33610.0851-0.3935-0.38830.6520.12260.4189-0.06940.00390.46170.00850.3684.5475-1.8546-45.8528
109.54911.67460.78412.23134.0098.03690.2553-0.49171.09521.0738-0.0517-0.3925-1.22770.696-0.30510.8661-0.2099-0.09640.7504-0.02170.551811.87097.0009-41.7479
114.0367-1.5979-1.65344.74020.48723.90720.071-0.1260.74-0.09470.1278-0.7399-1.1720.7901-0.16230.6708-0.2336-0.02440.5412-0.05930.55878.48898.7665-53.7757
126.63810.2582-1.79414.822-0.1491.5850.0953-0.32760.48260.42520.3663-0.0498-1.2832-0.2207-0.48850.59220.03830.02540.3647-0.0480.3659-6.13379.932-48.7868
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'D' and (resid 162 through 222 )
2X-RAY DIFFRACTION2chain 'D' and (resid 223 through 284 )
3X-RAY DIFFRACTION3chain 'D' and (resid 285 through 458 )
4X-RAY DIFFRACTION4chain 'A' and (resid 165 through 187 )
5X-RAY DIFFRACTION5chain 'A' and (resid 188 through 247 )
6X-RAY DIFFRACTION6chain 'A' and (resid 248 through 284 )
7X-RAY DIFFRACTION7chain 'A' and (resid 285 through 305 )
8X-RAY DIFFRACTION8chain 'A' and (resid 306 through 365 )
9X-RAY DIFFRACTION9chain 'A' and (resid 366 through 395 )
10X-RAY DIFFRACTION10chain 'A' and (resid 396 through 413 )
11X-RAY DIFFRACTION11chain 'A' and (resid 414 through 436 )
12X-RAY DIFFRACTION12chain 'A' and (resid 437 through 458 )

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