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- PDB-5uiq: Crystal structure of IRAK4 in complex with compound 9 -

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Basic information

Entry
Database: PDB / ID: 5uiq
TitleCrystal structure of IRAK4 in complex with compound 9
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
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 / 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 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
2-[(propan-2-yl)oxy]benzamide / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.64 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

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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)147,0538
Polymers146,3364
Non-polymers7174
Water1,13563
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7632
Polymers36,5841
Non-polymers1791
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)36,7632
Polymers36,5841
Non-polymers1791
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)36,7632
Polymers36,5841
Non-polymers1791
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)36,7632
Polymers36,5841
Non-polymers1791
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.058, 140.802, 87.986
Angle α, β, γ (deg.)90.00, 124.90, 90.00
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: 36584.020 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-8BV / 2-[(propan-2-yl)oxy]benzamide


Mass: 179.216 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H13NO2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.5 Å3/Da / Density % sol: 50.81 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 1.6-1.8 M 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 S 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: 2.64→20 Å / Num. obs: 39902 / % possible obs: 95.9 % / Redundancy: 3.1 % / Biso Wilson estimate: 63.22 Å2 / Net I/σ(I): 2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.64→19.86 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.923 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.713 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.6 / SU Rfree Blow DPI: 0.273 / SU Rfree Cruickshank DPI: 0.284
RfactorNum. reflection% reflectionSelection details
Rfree0.226 1946 4.88 %RANDOM
Rwork0.198 ---
obs0.199 39888 94.7 %-
Displacement parametersBiso mean: 59.78 Å2
Baniso -1Baniso -2Baniso -3
1--2.2512 Å20 Å2-1.0568 Å2
2--7.6851 Å20 Å2
3----5.4339 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: 1 / Resolution: 2.64→19.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8513 0 180 63 8756
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018830HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1411915HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3079SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes243HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1253HARMONIC5
X-RAY DIFFRACTIONt_it8830HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.59
X-RAY DIFFRACTIONt_other_torsion19.27
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1163SEMIHARMONIC5
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_contact9945SEMIHARMONIC4
LS refinement shellResolution: 2.64→2.71 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 139 5.53 %
Rwork0.238 2374 -
all0.239 2513 -
obs--81.04 %
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)
112.76714.50216.25752.13951.54774.3865-0.69030.78810.9256-0.95220.11050.6611-0.417-0.46410.57980.4516-0.0042-0.0880.4784-0.13770.428129.05727.4122-17.5823
22.02021.1456-0.91033.8758-1.00382.50630.03320.1577-0.0327-0.15390.0783-0.2766-0.40060.1248-0.1115-0.0267-0.03080.1128-0.18180.0138-0.208342.569119.8348-0.0518
36.08042.36363.98022.66423.94225.90340.5539-0.3176-1.1260.676-0.1185-0.94650.80620.2567-0.43530.1974-0.0874-0.14490.08320.10560.456348.7273-9.379816.5945
42.8674-0.6367-1.16264.09121.24012.8682-0.18390.2879-0.3343-0.28230.0411-0.10360.0243-0.02170.1427-0.138-0.03960.1143-0.2574-0.056-0.224127.0338-18.25747.3136
57.2166-1.77043.07481.785-2.84585.7220.41470.5524-0.6134-0.2248-0.20810.94530.5857-0.7727-0.20660.25230.1193-0.06930.3524-0.05380.3563-8.8262-8.632233.4546
62.13770.9669-0.96023.6797-0.93542.5053-0.0872-0.128-0.16360.15870.0715-0.11560.0491-0.0960.0157-0.1586-0.0110.0558-0.26520.0155-0.289212.1521-19.350741.8993
714.6015-1.91415.21500.01533.3014-0.5247-0.43251.09010.40590.3224-0.1941-0.35770.31550.20230.21620.0344-0.05240.03820.00020.136729.64958.830142.5081
81.798-0.5212-0.67093.28010.76663.3436-0.0151-0.066-0.0425-0.05420.08480.1847-0.368-0.1708-0.0697-0.10920.06810.0823-0.26570.0188-0.216714.435318.748924.6335
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|164 - A|263 }
2X-RAY DIFFRACTION2{ A|264 - A|458 }
3X-RAY DIFFRACTION3{ C|164 - C|263 }
4X-RAY DIFFRACTION4{ C|264 - C|458 }
5X-RAY DIFFRACTION5{ B|164 - B|263 }
6X-RAY DIFFRACTION6{ B|264 - B|458 }
7X-RAY DIFFRACTION7{ D|164 - D|263 }
8X-RAY DIFFRACTION8{ D|264 - D|458 }

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