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- PDB-6ti8: IRAK4 IN COMPLEX WITH inhibitor -

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Basic information

Entry
Database: PDB / ID: 6ti8
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-NBW / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 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 22, 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 1.2May 1, 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
C: Interleukin-1 receptor-associated kinase 4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,3428
Polymers138,5404
Non-polymers1,8024
Water7,134396
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0862
Polymers34,6351
Non-polymers4511
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)35,0862
Polymers34,6351
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0862
Polymers34,6351
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0862
Polymers34,6351
Non-polymers4511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.154, 110.532, 142.218
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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.: 4
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-NBW / ~{N},~{N}-dimethyl-4-(1-methylcyclopropyl)oxy-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrido[3,2-d]pyrimidine-6-carboxamide


Mass: 450.537 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H30N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 396 / 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: 2.53 Å3/Da / Density % sol: 51.36 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 2.7 M AMS 0.1 M Hepes pH 7.1-7.7 Protein Buffer: 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: ESRF / Beamline: ID29 / Wavelength: 1.072 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.32→49.66 Å / Num. obs: 61385 / % possible obs: 99.7 % / Redundancy: 6.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.044 / Rrim(I) all: 0.114 / Net I/σ(I): 11.1
Reflection shellResolution: 2.32→2.4 Å / Redundancy: 6.2 % / Rmerge(I) obs: 1.728 / Mean I/σ(I) obs: 1 / Num. unique obs: 5969 / CC1/2: 0.511 / Rpim(I) all: 0.748 / Rrim(I) all: 1.887 / % possible all: 99.6

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Processing

Software
NameVersionClassification
Aimless0.6.2data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal starting model

Resolution: 2.32→49.66 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.897 / SU R Cruickshank DPI: 0.368 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.378 / SU Rfree Blow DPI: 0.256 / SU Rfree Cruickshank DPI: 0.256
RfactorNum. reflection% reflectionSelection details
Rfree0.281 3070 5.01 %RANDOM
Rwork0.249 ---
obs0.25 61295 99.6 %-
Displacement parametersBiso max: 224.54 Å2 / Biso mean: 68.53 Å2 / Biso min: 26.59 Å2
Baniso -1Baniso -2Baniso -3
1--12.3377 Å20 Å20 Å2
2---3.1925 Å20 Å2
3---15.5303 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.32→49.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8961 0 132 396 9489
Biso mean--44.1 61.17 -
Num. residues----1135
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3284SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1592HARMONIC5
X-RAY DIFFRACTIONt_it9263HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1198SEMIHARMONIC5
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_contact10486SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9263HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12522HARMONIC21.26
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion20.08
LS refinement shellResolution: 2.32→2.38 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3857 207 4.65 %
Rwork0.3444 4245 -
all0.3463 4452 -
obs--99.35 %
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)
11.75640.3944-0.47647.20971.18753.4399-0.13460.1313-0.42990.54420.10130.0290.5442-0.1750.03330.0449-0.10230.0327-0.2335-0.0855-0.0247-118.79278.5305-24.8192
22.59610.2393-0.67151.1308-0.16422.27790.058-0.19880.02870.1850.0270.2445-0.0391-0.1073-0.0850.0089-0.020.026-0.1853-0.0056-0.0744-113.186231.8119-15.0585
32.5082-0.7587-1.09277.1372-0.77912.389-0.0113-0.1711-0.5084-0.4401-0.14120.00270.54420.11590.15250.0395-0.0165-0.085-0.21170.1207-0.0758-56.70929.5454-45.6156
42.4415-0.2515-0.90720.8844-0.33883.10410.16570.18040.0450.0385-0.1159-0.2385-0.29620.1898-0.0498-0.0477-0.02160.0171-0.13270.0083-0.0787-63.255332.377-56.0839
52.04810.77690.76284.68772.20192.48180.07980.10730.3638-0.40030.00720.1428-0.54420.0682-0.0870.0074-0.08980.0679-0.115-0.0394-0.0907-104.412344.6381-44.8489
63.6016-0.61320.0041.40990.34371.78940.2640.0709-0.3563-0.1215-0.2240.18890.2346-0.1014-0.04-0.0179-0.0386-0.0574-0.1526-0.0304-0.0905-98.874921.5513-54.0639
73.5783-0.47581.12544.9686-1.74830-0.1197-0.32210.32770.2178-0.0012-0.1119-0.12430.05920.12090.0812-0.0640.0011-0.10450.0262-0.1826-71.746245.3231-26.0172
83.2870.56810.18711.3819-0.41472.740.2846-0.2052-0.36960.1398-0.2596-0.23410.04920.172-0.0250.0221-0.0118-0.0683-0.1870.0511-0.0798-77.089222.1482-16.9862
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|165 - A|265 }A165 - 265
2X-RAY DIFFRACTION2{ A|266 - A|459 }A266 - 459
3X-RAY DIFFRACTION3{ B|165 - B|265 }B165 - 265
4X-RAY DIFFRACTION4{ B|266 - B|459 }B266 - 459
5X-RAY DIFFRACTION5{ C|164 - C|265 }C164 - 265
6X-RAY DIFFRACTION6{ C|266 - C|459 }C266 - 459
7X-RAY DIFFRACTION7{ D|164 - D|265 }D164 - 265
8X-RAY DIFFRACTION8{ D|266 - D|458 }D266 - 458

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