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- PDB-5uis: Crystal structure of IRAK4 in complex with compound 12 -

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Basic information

Entry
Database: PDB / ID: 5uis
TitleCrystal structure of IRAK4 in complex with compound 12
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE / IRAK4 / Kinase / Fragment Screening
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 / Toll signaling pathway / MyD88 cascade initiated on plasma membrane / 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 / Toll signaling pathway / MyD88 cascade initiated on plasma membrane / 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 / lipopolysaccharide-mediated signaling pathway / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / kinase activity / PIP3 activates AKT signaling / eukaryotic translation initiation factor 2alpha kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / Rho-dependent protein serine/threonine kinase activity / ribosomal protein S6 kinase activity / histone H2BS14 kinase activity / histone H3T6 kinase activity / histone H3T45 kinase activity / histone H3S10 kinase activity / histone H3T11 kinase activity / AMP-activated protein kinase activity / positive regulation of canonical NF-kappaB signal transduction / histone H2AS1 kinase activity / non-specific serine/threonine protein kinase / intracellular signal transduction / endosome membrane / protein serine/threonine kinase activity / innate immune response / protein serine 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-8C1 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsHan, S. / Chang, J.S.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 ...Title: Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.
Authors: Lee, K.L. / Ambler, C.M. / Anderson, D.R. / Boscoe, B.P. / Bree, A.G. / Brodfuehrer, J.I. / Chang, J.S. / Choi, C. / Chung, S. / Curran, K.J. / Day, J.E. / Dehnhardt, C.M. / Dower, K. / ...Authors: Lee, K.L. / Ambler, C.M. / Anderson, D.R. / Boscoe, B.P. / Bree, A.G. / Brodfuehrer, J.I. / Chang, J.S. / Choi, C. / Chung, S. / Curran, K.J. / Day, J.E. / Dehnhardt, C.M. / Dower, K. / Drozda, S.E. / Frisbie, R.K. / Gavrin, L.K. / Goldberg, J.A. / Han, S. / Hegen, M. / Hepworth, D. / Hope, H.R. / Kamtekar, S. / Kilty, I.C. / Lee, A. / Lin, L.L. / Lovering, F.E. / Lowe, M.D. / Mathias, J.P. / Morgan, H.M. / Murphy, E.A. / Papaioannou, N. / Patny, A. / Pierce, B.S. / Rao, V.R. / Saiah, E. / Samardjiev, I.J. / Samas, B.M. / Shen, M.W.H. / Shin, J.H. / Soutter, H.H. / Strohbach, J.W. / Symanowicz, P.T. / Thomason, J.R. / Trzupek, J.D. / Vargas, R. / Vincent, F. / Yan, J. / Zapf, C.W. / Wright, S.W.
History
DepositionJan 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: 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 1.2Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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)147,3348
Polymers146,0164
Non-polymers1,3184
Water2,468137
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8332
Polymers36,5041
Non-polymers3291
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)36,8332
Polymers36,5041
Non-polymers3291
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)36,8332
Polymers36,5041
Non-polymers3291
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)36,8332
Polymers36,5041
Non-polymers3291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.141, 141.129, 87.435
Angle α, β, γ (deg.)90.00, 124.72, 90.00
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: 36504.039 Da / Num. of mol.: 4 / Fragment: UNP residues 154-460
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-8C1 / 4-{[(3R)-piperidin-3-yl]oxy}-6-[(propan-2-yl)oxy]quinoline-7-carboxamide


Mass: 329.394 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H23N3O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O
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: 2.49 Å3/Da / Density % sol: 50.52 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 1.6-1.6M Ammonium Citrate, pH 7.0

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Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 48886 / % possible obs: 99.9 % / Redundancy: 3.7 % / Biso Wilson estimate: 61.94 Å2 / Net I/σ(I): 11.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.5→25.36 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.911 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.463 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.425 / SU Rfree Blow DPI: 0.254 / SU Rfree Cruickshank DPI: 0.263
RfactorNum. reflection% reflectionSelection details
Rfree0.25 2517 5.16 %RANDOM
Rwork0.234 ---
obs0.235 48762 99 %-
Displacement parametersBiso mean: 52.38 Å2
Baniso -1Baniso -2Baniso -3
1--3.635 Å20 Å2-4.3765 Å2
2--6.4066 Å20 Å2
3----2.7716 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: 1 / Resolution: 2.5→25.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8410 0 96 137 8643
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0098745HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.111858HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3103SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes239HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1304HARMONIC5
X-RAY DIFFRACTIONt_it8745HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion18.38
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1127SEMIHARMONIC5
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_contact9956SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.56 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.271 191 5.85 %
Rwork0.275 3072 -
all0.275 3263 -
obs--90.44 %
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)
11.05570.22530.27961.63090.30882.6833-0.03240.0759-0.0470.00550.0795-0.0419-0.34210.1713-0.0471-0.0781-0.04750.0599-0.18460.0112-0.112527.31119.56375.9679
22.6095-0.2061-0.41481.7019-0.28621.1988-0.1623-0.2639-0.37190.11990.07280.09540.04650.00370.0895-0.09060.00440.0715-0.19610.0442-0.087213.034-20.925425.608
32.4787-0.4671-0.80251.90230.03972.1220.01870.0632-0.1548-0.0515-0.0497-0.1209-0.07160.2540.031-0.16690.00960.0473-0.15040.0042-0.111540.5559-21.1836-2.6308
41.74780.0287-0.50692.58410.26662.042-0.0544-0.2513-0.05810.14170.01580.0952-0.2307-0.06490.0386-0.07630.02870.0453-0.1385-0.0166-0.19588.162410.400640.1952
50.536-0.4357-0.0570.97980.1880.4980.0329-0.0989-0.05350.0551-0.0959-0.0351-0.07950.07440.0630.0175-0.0788-0.01720.01260.00220.019422.4995-5.681617.3606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|165 - A|458 }
2X-RAY DIFFRACTION2{ B|165 - B|458 }
3X-RAY DIFFRACTION3{ C|162 - C|458 }
4X-RAY DIFFRACTION4{ D|165 - D|458 }
5X-RAY DIFFRACTION5{ A|800 - A|800 C|501 - C|501 B|801 - B|801 D|501 - D|501 }

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