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- PDB-6lxy: IRAK4 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6lxy
TitleIRAK4 in complex with inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4IRAK4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / IRAK4 / KINASE / INHIBITOR / CANCER / SIGNALING PROTEIN / 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) / 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 / 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
Chem-EXF / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsGhosh, K. / Bose, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.
Authors: Nair, S. / Kumar, S.R. / Paidi, V.R. / Sistla, R. / Kantheti, D. / Polimera, S.R. / Thangavel, S. / Mukherjee, A.J. / Das, M. / Bhide, R.S. / Pitts, W.J. / Murugesan, N. / Dudhgoankar, S. / ...Authors: Nair, S. / Kumar, S.R. / Paidi, V.R. / Sistla, R. / Kantheti, D. / Polimera, S.R. / Thangavel, S. / Mukherjee, A.J. / Das, M. / Bhide, R.S. / Pitts, W.J. / Murugesan, N. / Dudhgoankar, S. / Nagar, J. / Subramani, S. / Mazumder, D. / Carman, J.A. / Holloway, D.A. / Li, X. / Fereshteh, M.P. / Ruepp, S. / Palanisamy, K. / Mariappan, T.T. / Maddi, S. / Saxena, A. / Elzinga, P. / Chimalakonda, A. / Ruan, Q. / Ghosh, K. / Bose, S. / Sack, J. / Yan, C. / Kiefer, S.E. / Xie, D. / Newitt, J.A. / Saravanakumar, S.P. / Rampulla, R.A. / Barrish, J.C. / Carter, P.H. / Hynes Jr., J.
History
DepositionFeb 12, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release

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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
D: Interleukin-1 receptor-associated kinase 4
E: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,79211
Polymers136,7704
Non-polymers2,0227
Water5,080282
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6262
Polymers34,1931
Non-polymers4331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13340 Å2
MethodPISA
2
B: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7223
Polymers34,1931
Non-polymers5302
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-11 kcal/mol
Surface area13560 Å2
MethodPISA
3
D: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7223
Polymers34,1931
Non-polymers5302
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13260 Å2
MethodPISA
4
E: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7223
Polymers34,1931
Non-polymers5302
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.670, 140.810, 86.280
Angle α, β, γ (deg.)90.000, 125.700, 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: 34192.586 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-EXF / N-[(2R)-2-fluoranyl-3-methyl-3-oxidanyl-butyl]-6-[(6-fluoranylpyrazolo[1,5-a]pyrimidin-5-yl)amino]-4-(propan-2-ylamino)pyridine-3-carboxamide


Mass: 433.455 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H25F2N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 282 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.45 Å3/Da / Density % sol: 49.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: Ammonium sulphate / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Aug 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 64970 / % possible obs: 97.3 % / Redundancy: 3.6 % / Biso Wilson estimate: 30.7 Å2 / Rmerge(I) obs: 0.116 / Χ2: 1.043 / Net I/σ(I): 7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.2-2.283.10.53958181.056187.1
2.28-2.373.20.49360721.011191.7
2.37-2.483.40.42663951.031196.1
2.48-2.613.60.36965561.019198.5
2.61-2.773.80.3166811.073199.9
2.77-2.993.80.22566661.0741100
2.99-3.293.80.14366661.0461100
3.29-3.763.80.09266981.053199.9
3.76-4.743.70.0766641.049199.8
4.74-503.70.0667541.009199.6

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
BUSTERrefinement
PDB_EXTRACT3.25data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.19→48.08 Å / Cor.coef. Fo:Fc: 0.898 / Cor.coef. Fo:Fc free: 0.871 / SU R Cruickshank DPI: 0.251 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.242 / SU Rfree Blow DPI: 0.186 / SU Rfree Cruickshank DPI: 0.191
RfactorNum. reflection% reflectionSelection details
Rfree0.231 3252 5.01 %RANDOM
Rwork0.201 ---
obs0.202 64957 96.5 %-
Displacement parametersBiso max: 141.46 Å2 / Biso mean: 43.27 Å2 / Biso min: 13.42 Å2
Baniso -1Baniso -2Baniso -3
1--10.4354 Å20 Å2-18.3719 Å2
2--13.4025 Å20 Å2
3----2.9671 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.19→48.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8712 0 139 282 9133
Biso mean--36.57 43.09 -
Num. residues----1172
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2975SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1629HARMONIC5
X-RAY DIFFRACTIONt_it9009HARMONIC20
X-RAY DIFFRACTIONt_chiral_improper_torsion1233SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact10366SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9009HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg12263HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion2.76
X-RAY DIFFRACTIONt_other_torsion17.03
LS refinement shellResolution: 2.19→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2803 60 4.62 %
Rwork0.2753 1240 -
all0.2755 1300 -
obs--61.81 %

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