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- PDB-5uiu: Crystal structure of IRAK4 in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 5uiu
TitleCrystal structure of IRAK4 in complex with compound 30
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE / IRAK4 / Kinase
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) / toll-like receptor 4 signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / 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 / 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 / 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-8CG / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.02 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

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Assembly

Deposited unit
A: Interleukin-1 receptor-associated kinase 4
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,8914
Polymers73,1682
Non-polymers7232
Water7,080393
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9452
Polymers36,5841
Non-polymers3611
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)36,9452
Polymers36,5841
Non-polymers3611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.940, 118.460, 138.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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.: 2 / 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-8CG / 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide


Mass: 361.368 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20FN3O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 393 / 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: 2.53 Å3/Da / Density % sol: 51.33 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 1.6-1.8M Ammonium Citrate, pH7.0

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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, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→75.5 Å / Num. obs: 49042 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 37.41 Å2 / Net I/σ(I): 23.4

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementResolution: 2.02→75.49 Å / Cor.coef. Fo:Fc: 0.9438 / Cor.coef. Fo:Fc free: 0.9319 / SU R Cruickshank DPI: 0.156 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.163 / SU Rfree Blow DPI: 0.134 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflectionSelection details
Rfree0.2044 2472 5.06 %RANDOM
Rwork0.1854 ---
obs0.1863 48890 99.91 %-
Displacement parametersBiso mean: 46.34 Å2
Baniso -1Baniso -2Baniso -3
1--2.0648 Å20 Å20 Å2
2---6.6063 Å20 Å2
3---8.6711 Å2
Refine analyzeLuzzati coordinate error obs: 0.247 Å
Refinement stepCycle: 1 / Resolution: 2.02→75.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4511 0 52 393 4956
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014750HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.096460HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1685SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes134HARMONIC2
X-RAY DIFFRACTIONt_gen_planes719HARMONIC5
X-RAY DIFFRACTIONt_it4750HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion17.44
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion619SEMIHARMONIC5
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_contact5683SEMIHARMONIC4
LS refinement shellResolution: 2.02→2.07 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2034 171 4.74 %
Rwork0.1954 3435 -
all0.1958 3606 -
obs--99.91 %
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)
12.11650.6795-0.23231.2706-0.10861.45660.0774-0.0515-0.13340.105-0.04460.13310.0063-0.1807-0.0329-0.28180.0410.0143-0.22330.0184-0.2729-27.5264-31.902814.5714
21.524-0.22810.69911.00550.23732.2045-0.08960.1040.075-0.1204-0.02470.0816-0.2943-0.02430.1143-0.2174-0.0296-0.0381-0.27640.0156-0.2806-11.8731-24.8002-15.5647
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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