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- PDB-6ega: IRAK4 in complex with a type II inhibitor -

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Basic information

Entry
Database: PDB / ID: 6ega
TitleIRAK4 in complex with a type II inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Complex / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 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-J8A / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.512 Å
AuthorsWang, L. / Wu, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI050872 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 20, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 4, 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 1.2Nov 20, 2019Group: Derived calculations / Category: pdbx_struct_conn_angle / struct_conn
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,35012
Polymers69,6432
Non-polymers1,70710
Water79344
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules

B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,35012
Polymers69,6432
Non-polymers1,70710
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_565x-y,-y+1,-z1
Buried area1960 Å2
ΔGint-53 kcal/mol
Surface area25490 Å2
MethodPISA
2
A: Interleukin-1 receptor-associated kinase 4
hetero molecules

A: Interleukin-1 receptor-associated kinase 4
hetero molecules

B: Interleukin-1 receptor-associated kinase 4
hetero molecules

B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,70024
Polymers139,2864
Non-polymers3,41420
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_565x,x-y+1,-z+1/61
crystal symmetry operation6_555x-y,x,z+1/61
crystal symmetry operation8_565x-y,-y+1,-z1
Buried area7720 Å2
ΔGint-128 kcal/mol
Surface area47430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.629, 84.629, 429.041
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11B-504-

CO

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Components

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


Mass: 34821.453 Da / Num. of mol.: 2 / Fragment: Protein kinase domain 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-J8A / 3-{2-[(cyclopropanecarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}-N-{4-[(piperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide


Mass: 580.624 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Co
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 3.18 Å3/Da / Density % sol: 61.37 %
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 8
Details: 0.1M Tris-Hcl pH 8.0 1.5M-1.6M ammonium sulfate 20mM Cobalt chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.51→143 Å / Num. obs: 32497 / % possible obs: 99.4 % / Redundancy: 35.2 % / Net I/σ(I): 21.7
Reflection shellResolution: 2.51→2.59 Å

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.512→73.291 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.05
RfactorNum. reflection% reflection
Rfree0.2669 1646 5.1 %
Rwork0.2298 --
obs0.2317 32264 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.512→73.291 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4219 0 98 44 4361
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044412
X-RAY DIFFRACTIONf_angle_d0.8675957
X-RAY DIFFRACTIONf_dihedral_angle_d15.5021697
X-RAY DIFFRACTIONf_chiral_restr0.027657
X-RAY DIFFRACTIONf_plane_restr0.003763
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5123-2.58620.36271200.36422316X-RAY DIFFRACTION93
2.5862-2.66970.37521310.38232507X-RAY DIFFRACTION100
2.6697-2.76510.4151230.34912504X-RAY DIFFRACTION100
2.7651-2.87590.35371530.3232487X-RAY DIFFRACTION100
2.8759-3.00680.33681360.28672508X-RAY DIFFRACTION100
3.0068-3.16530.28371190.28192526X-RAY DIFFRACTION100
3.1653-3.36360.27561580.27212527X-RAY DIFFRACTION100
3.3636-3.62330.29391270.23792545X-RAY DIFFRACTION100
3.6233-3.98790.24581380.21312579X-RAY DIFFRACTION100
3.9879-4.56490.24461340.18642602X-RAY DIFFRACTION100
4.5649-5.75090.25211450.20592653X-RAY DIFFRACTION100
5.7509-73.3220.23811620.20592864X-RAY DIFFRACTION100

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