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- PDB-7qg2: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 7qg2
TitleIRAK4 in complex with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / Kinase inhibitor Interleukin-1 Receptor-Associated Kinase 4 Interleukin-1 signaling
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 / 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 / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-B6I / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.031 Å
AuthorsXue, Y. / Aagaard, A. / Robb, G.R. / Degorce, S.L.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Other private Sweden
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.
Authors: Cumming, I.A. / Degorce, S.L. / Aagaard, A. / Braybrooke, E.L. / Davies, N.L. / Diene, C.R. / Eatherton, A.J. / Felstead, H.R. / Groombridge, S.D. / Lenz, E.M. / Li, Y. / Nai, Y. / Pearson, ...Authors: Cumming, I.A. / Degorce, S.L. / Aagaard, A. / Braybrooke, E.L. / Davies, N.L. / Diene, C.R. / Eatherton, A.J. / Felstead, H.R. / Groombridge, S.D. / Lenz, E.M. / Li, Y. / Nai, Y. / Pearson, S. / Robb, G.R. / Scott, J.S. / Steward, O.R. / Wu, C. / Xue, Y. / Zhang, L. / Zhang, Y.
History
DepositionDec 7, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)140,1748
Polymers138,5404
Non-polymers1,6344
Water2,072115
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0442
Polymers34,6351
Non-polymers4091
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)35,0442
Polymers34,6351
Non-polymers4091
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)35,0442
Polymers34,6351
Non-polymers4091
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)35,0442
Polymers34,6351
Non-polymers4091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)141.39, 139.72, 87.27
Angle α, β, γ (deg.)90, 123.62, 90
Int Tables number5
Space group name H-MC121

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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
Details: the kinase domain / 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-B6I / 6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one


Mass: 408.500 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.59 Å3/Da / Density % sol: 52.52 %
Crystal growTemperature: 298 K / Method: evaporation / Details: 2.5 M AMS, 0.1 M Hepes pH 7.67

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 3.03→72.67 Å / Num. obs: 26624 / % possible obs: 99.4 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 7.8
Reflection shellResolution: 3.03→3.08 Å / Rmerge(I) obs: 0.486 / Mean I/σ(I) obs: 3 / Num. unique obs: 1336 / % possible all: 99.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
Aimlessdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6RFJ

6rfj


Resolution: 3.031→72.67 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.894 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.472
RfactorNum. reflection% reflectionSelection details
Rfree0.2739 1312 -RANDOM
Rwork0.2243 ---
obs0.2267 26624 97 %-
Displacement parametersBiso mean: 64.85 Å2
Baniso -1Baniso -2Baniso -3
1--4.8119 Å20 Å2-4.3752 Å2
2--10.0568 Å20 Å2
3----5.245 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: LAST / Resolution: 3.031→72.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8856 0 120 115 9091
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089145HARMONIC2
X-RAY DIFFRACTIONt_angle_deg112356HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3242SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1567HARMONIC5
X-RAY DIFFRACTIONt_it9145HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1177SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact7489SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion18.54
LS refinement shellResolution: 3.031→3.05 Å
RfactorNum. reflection% reflection
Rfree0.3238 40 -
Rwork0.3029 --
obs--100 %
Refinement TLS params.

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)
11.3542-0.94030.08552.2945-0.13421.9247-0.02850.1857-0.2060.18570.11090.021-0.2060.021-0.08230.05860.02110.162-0.1084-0.0445-0.0613-37.343414.64435.8277
21.63050.3187-0.32941.83240.12532.2360.0532-0.2326-0.0533-0.2326-0.15550.2949-0.05330.29490.10230.00330.03840.1896-0.12460.00290.0163-6.486-15.0525-39.557
31.8087-0.66670.41782.5905-1.19781.39-0.1958-0.10490.1045-0.10490.165-0.08910.1045-0.08910.03080.095-0.00580.1862-0.20120.0451-0.0055-33.7795-15.9764-11.3566
41.25850.82850.30091.4370.17712.3950.1161-0.0353-0.2727-0.03530.11860.187-0.27270.187-0.23470.0945-0.01770.221-0.2083-0.00480.0178-19.699815.853-29.6154
5-0.1317-1.1219-0.02440.1419-0.11920.37140.0633-0.118-0.0876-0.1180.3133-0.0337-0.0876-0.0337-0.37660.0301-0.12440.0460.0480.09310.1551-24.3611-0.2462-18.8304
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A164 - 458
2X-RAY DIFFRACTION2{ B|* }B165 - 458
3X-RAY DIFFRACTION3{ C|* }C164 - 458
4X-RAY DIFFRACTION4{ D|* }D164 - 458

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