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- PDB-6o95: Structure of the IRAK4 kinase domain with compound 41 -

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Basic information

Entry
Database: PDB / ID: 6o95
TitleStructure of the IRAK4 kinase domain with compound 41
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsIMMUNE SYSTEM / kinase / IRAK4 / IRAK1 / IRAK2 / IRAK3
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 / 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 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-LSV / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 Å
AuthorsYu, C. / Drobnick, J. / Bryan, M.C. / Kiefer, J. / Lupardus, P.J.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.
Authors: Bryan, M.C. / Drobnick, J. / Gobbi, A. / Kolesnikov, A. / Chen, Y. / Rajapaksa, N. / Ndubaku, C. / Feng, J. / Chang, W. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. / Ran, Y. / An, L. / ...Authors: Bryan, M.C. / Drobnick, J. / Gobbi, A. / Kolesnikov, A. / Chen, Y. / Rajapaksa, N. / Ndubaku, C. / Feng, J. / Chang, W. / Francis, R. / Yu, C. / Choo, E.F. / DeMent, K. / Ran, Y. / An, L. / Emson, C. / Huang, Z. / Sujatha-Bhaskar, S. / Brightbill, H. / DiPasquale, A. / Maher, J. / Wai, J. / McKenzie, B.S. / Lupardus, P.J. / Zarrin, A.A. / Kiefer, J.R.
History
DepositionMar 13, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1May 29, 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jul 24, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Apr 3, 2024Group: 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

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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)146,60811
Polymers144,6824
Non-polymers1,9267
Water15,061836
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6763
Polymers36,1711
Non-polymers5062
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)36,5802
Polymers36,1711
Non-polymers4091
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)36,5802
Polymers36,1711
Non-polymers4091
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)36,7724
Polymers36,1711
Non-polymers6023
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.838, 140.615, 87.559
Angle α, β, γ (deg.)90.00, 123.71, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 36170.531 Da / Num. of mol.: 4 / Fragment: residues 160-460
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-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-LSV / N-[(2R)-2-(hydroxymethyl)-2-methyl-6-(morpholin-4-yl)-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 409.438 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H23N5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 836 / 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: 2.51 Å3/Da / Density % sol: 51 %
Crystal growMethod: vapor diffusion / Details: 2.6-2.9 M Ammonium Sulfate, Hepes

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.77→72.84 Å / Num. obs: 138183 / % possible obs: 99.5 % / Redundancy: 3.7 % / Biso Wilson estimate: 29.6 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.037 / Net I/σ(I): 17.2
Reflection shellResolution: 1.77→1.86 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.475 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 20270 / CC1/2: 0.806 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house

Resolution: 1.77→72.84 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.939 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.106 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.109 / SU Rfree Blow DPI: 0.104 / SU Rfree Cruickshank DPI: 0.103
RfactorNum. reflection% reflectionSelection details
Rfree0.217 6866 4.98 %RANDOM
Rwork0.188 ---
obs0.19 137785 99.5 %-
Displacement parametersBiso mean: 34.34 Å2
Baniso -1Baniso -2Baniso -3
1-0.3554 Å20 Å2-1.5053 Å2
2--3.1597 Å20 Å2
3----3.5151 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: 1 / Resolution: 1.77→72.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8932 0 252 836 10020
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019367HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.3112679HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3341SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes271HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1404HARMONIC5
X-RAY DIFFRACTIONt_it9367HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.15
X-RAY DIFFRACTIONt_other_torsion16.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1228SEMIHARMONIC5
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_contact11635SEMIHARMONIC4
LS refinement shellResolution: 1.77→1.82 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 467 4.55 %
Rwork0.221 9789 -
all0.222 10256 -
obs--99.93 %

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