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- PDB-5k72: IRAK4 in complex with Compound 21 -

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Basic information

Entry
Database: PDB / ID: 5k72
TitleIRAK4 in complex with Compound 21
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Kinase / Protein tyrosine kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / Interleukin-1 signaling / cytokine-mediated signaling pathway / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/Threonine protein kinases, catalytic domain ...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 / 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-6QY / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsFerguson, A.D.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma.
Authors: Scott, J.S. / Degorce, S.L. / Anjum, R. / Culshaw, J. / Davies, R.D.M. / Davies, N.L. / Dillman, K.S. / Dowling, J.E. / Drew, L. / Ferguson, A.D. / Groombridge, S.D. / Halsall, C.T. / ...Authors: Scott, J.S. / Degorce, S.L. / Anjum, R. / Culshaw, J. / Davies, R.D.M. / Davies, N.L. / Dillman, K.S. / Dowling, J.E. / Drew, L. / Ferguson, A.D. / Groombridge, S.D. / Halsall, C.T. / Hudson, J.A. / Lamont, S. / Lindsay, N.A. / Marden, S.K. / Mayo, M.F. / Pease, J.E. / Perkins, D.R. / Pink, J.H. / Robb, G.R. / Rosen, A. / Shen, M. / McWhirter, C. / Wu, D.
History
DepositionMay 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2018Group: 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 1.2Sep 27, 2023Group: 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)137,35913
Polymers135,5054
Non-polymers1,8549
Water5,242291
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4124
Polymers33,8761
Non-polymers5363
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)34,5085
Polymers33,8761
Non-polymers6324
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)34,2202
Polymers33,8761
Non-polymers3431
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)34,2202
Polymers33,8761
Non-polymers3431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.084, 140.968, 87.522
Angle α, β, γ (deg.)90.000, 125.770, 90.000
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: 33876.215 Da / Num. of mol.: 4 / Fragment: UNP 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.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-6QY / ~{N}4,~{N}4-dimethyl-~{N}1-[5-(oxan-4-yl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine


Mass: 343.466 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H29N5O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 2.69 Å3/Da / Density % sol: 54.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 2.5 M ammonium sulfate, 0.1 M Hepes pH 7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.22→70.48 Å / Num. obs: 69626 / % possible obs: 99.6 % / Redundancy: 4.1 % / Biso Wilson estimate: 49.31 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.036 / Rrim(I) all: 0.075 / Net I/σ(I): 12.9 / Num. measured all: 286999
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.22-2.574.20.479199.9
4.45-70.4840.033198.3

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Processing

Software
NameVersionClassification
Aimless0.3.5data scaling
BUSTER-TNT2.11.7refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NRU

2nru


Resolution: 2.22→58.86 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.251 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.243 / SU Rfree Blow DPI: 0.177 / SU Rfree Cruickshank DPI: 0.181
RfactorNum. reflection% reflectionSelection details
Rfree0.225 3419 4.91 %RANDOM
Rwork0.215 ---
obs0.215 69618 99 %-
Displacement parametersBiso max: 189.1 Å2 / Biso mean: 63.49 Å2 / Biso min: 25.64 Å2
Baniso -1Baniso -2Baniso -3
1--4.0243 Å20 Å2-5.1281 Å2
2--6.4443 Å20 Å2
3----2.42 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.22→58.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8730 0 125 291 9146
Biso mean--57.85 50.89 -
Num. residues----1103
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3238SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes257HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1250HARMONIC5
X-RAY DIFFRACTIONt_it9007HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1160SEMIHARMONIC5
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_contact10502SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9007HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12150HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion18.04
LS refinement shellResolution: 2.22→2.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.217 218 4.61 %
Rwork0.217 4514 -
all-4732 -
obs--91.48 %
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)
12.70660.3093-0.52172.6538-0.41461.4735-0.0355-0.0318-0.20730.07360.02480.0582-0.0481-0.26560.0107-0.1905-0.00240.0267-0.22050.02-0.1634-41-15.0762.698
21.66430.6508-0.25362.8757-0.21973.3083-0.16820.3499-0.0138-0.29430.1468-0.1081-0.1739-0.01640.0214-0.1591-0.04320.0245-0.20950.0164-0.2197-8.65615.246-40.012
31.23160.4437-0.11014.1346-0.76153.0115-0.0024-0.1353-0.14090.3324-0.1046-0.3707-0.4548-0.17580.107-0.15350.0501-0.0396-0.2950.0208-0.1515-27.40715.637-5.558
43.30911.4738-0.67155.4382-1.12361.6853-0.04980.2123-0.4770.2434-0.1857-0.534-0.10130.07510.2355-0.1923-0.0379-0.0239-0.3071-0.0521-0.1688-13.087-15.379-24.882
50.1246-0.3484-0.041600.6726-0.12460.05690.0526-0.1063-0.00260.0485-0.031-0.114-0.0575-0.1054-0.0089-0.0314-0.1063-0.090.05880.0522-22.5070.009-16.928
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|164 - A|458 }A164 - 458
2X-RAY DIFFRACTION2{ B|165 - B|458 }B165 - 458
3X-RAY DIFFRACTION3{ C|164 - C|458 }C164 - 458
4X-RAY DIFFRACTION4{ D|164 - D|458 }D164 - 458
5X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|504 - B|504 D|501 - D|501 }A503
6X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|504 - B|504 D|501 - D|501 }C501
7X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|504 - B|504 D|501 - D|501 }B504
8X-RAY DIFFRACTION5{ A|503 - A|503 C|501 - C|501 B|504 - B|504 D|501 - D|501 }D501

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