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- PDB-6thx: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6thx
TitleIRAK4 in complex with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsSIGNALING PROTEIN / IRAK4 / kinase / inhibitor / cancer
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-N9Z / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsXue, Y. / Aagaard, A. / Degorce, S.L.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.
Authors: Degorce, S.L. / Aagaard, A. / Anjum, R. / Cumming, I.A. / Diene, C.R. / Fallan, C. / Johnson, T. / Leuchowius, K.J. / Orton, A.L. / Pearson, S. / Robb, G.R. / Rosen, A. / Scarfe, G.B. / ...Authors: Degorce, S.L. / Aagaard, A. / Anjum, R. / Cumming, I.A. / Diene, C.R. / Fallan, C. / Johnson, T. / Leuchowius, K.J. / Orton, A.L. / Pearson, S. / Robb, G.R. / Rosen, A. / Scarfe, G.B. / Scott, J.S. / Smith, J.M. / Steward, O.R. / Terstiege, I. / Tucker, M.J. / Turner, P. / Wilkinson, S.D. / Wrigley, G.L. / Xue, Y.
History
DepositionNov 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 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 1.2Jan 24, 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

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)69,9394
Polymers69,2702
Non-polymers6692
Water3,675204
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9692
Polymers34,6351
Non-polymers3341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9692
Polymers34,6351
Non-polymers3341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.880, 109.230, 142.180
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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


Mass: 34635.008 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Residue TPO is phosphorylated THR, residue SEP is phosphorylated SER.
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-N9Z / 2-[4-[(1-methylcyclopropyl)amino]-2-[(1-methylpyrazol-4-yl)amino]pyrido[3,2-d]pyrimidin-6-yl]ethanenitrile


Mass: 334.378 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.68 Å3/Da / Density % sol: 54.17 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 25 mM HEPES pH 7.5, 1 mM EDTA, 1 mM TCEP, 5% Glycerol, 150 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Mar 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.99→86.62 Å / Num. obs: 46995 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.023 / Rrim(I) all: 0.059 / Net I/σ(I): 14.2
Reflection shellResolution: 1.99→2.04 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.587 / Mean I/σ(I) obs: 3 / Num. unique obs: 3427 / Rpim(I) all: 0.247 / Rrim(I) all: 0.638 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimless0.5.21data scaling
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6rfj

6rfj


Resolution: 1.99→71.09 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.187 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.188 / SU Rfree Blow DPI: 0.159 / SU Rfree Cruickshank DPI: 0.159
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2360 5.02 %RANDOM
Rwork0.231 ---
obs0.232 46993 100 %-
Displacement parametersBiso max: 181.95 Å2 / Biso mean: 66.54 Å2 / Biso min: 29.55 Å2
Baniso -1Baniso -2Baniso -3
1--3.5713 Å20 Å20 Å2
2---7.4282 Å20 Å2
3---10.9995 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 1.99→71.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4445 0 50 204 4699
Biso mean--50.06 56.98 -
Num. residues----562
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1626SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes790HARMONIC5
X-RAY DIFFRACTIONt_it4575HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion590SEMIHARMONIC5
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_contact5540SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4575HARMONIC20.012
X-RAY DIFFRACTIONt_angle_deg6178HARMONIC21.21
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion21.21
LS refinement shellResolution: 1.99→2.01 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2598 56 5.96 %
Rwork0.2491 884 -
all0.2497 940 -
obs--100 %
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)
11.9025-0.2951-0.69641.00240.22923.8385-0.0426-0.0435-0.2485-0.06240.0716-0.22290.54420.3063-0.029-0.02490.11340.0189-0.17810.0205-0.1644-17.2232-30.4786-16.7499
21.9785-0.236-0.58311.6121-0.24422.57720.3151-0.0251-0.1061-0.0206-0.22910.23820.0236-0.0276-0.086-0.0302-0.0523-0.0333-0.0668-0.0806-0.2416-56.4303-25.3419-15.2341
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A164 - 458
2X-RAY DIFFRACTION2{ B|* }B164 - 458

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