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- PDB-8scw: Crystal structure of IRAK4-HSA complexed with BMS-986147; 6-{5-CY... -

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Basic information

Entry
Database: PDB / ID: 8scw
TitleCrystal structure of IRAK4-HSA complexed with BMS-986147; 6-{5-CYANO-1H-PYRAZOLO[3,4-B]PYRIDIN-1-YL}-N-[(2R)-2-FLUORROXY-3-METHYLBUTYL]-4-[(PROPAN-2-YL)AMINO]PYRIDINE-3-CARBOXAMIDE
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / IRAK4 / ligand / 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 / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / interleukin-1 receptor binding / neutrophil mediated immunity ...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 / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / interleukin-1 receptor binding / neutrophil mediated immunity / interleukin-1-mediated signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / extrinsic component of plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / JNK cascade / positive regulation of smooth muscle cell proliferation / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / lipopolysaccharide-mediated signaling pathway / Interleukin-1 signaling / cytokine-mediated signaling pathway / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of canonical NF-kappaB signal transduction / non-specific serine/threonine protein kinase / endosome membrane / intracellular signal transduction / 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 / cytoplasm / cytosol
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 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsMuckelbauer, J.K. / Ghosh, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: The Discovery of IRAK4 Inhibitor Clinical Candidates BMS-986126 and BMS-986147 for the Treatment of Autoimmune Diseases
Authors: Kumar, S.R. / Dudhgoankar, S. / Santella, J.B. / Paidi, V.R.R. / Nair, S. / Sistla, R. / Wu, H. / Gardner, D.S. / Stachura, S. / Cavallaro, C.L. / Brown, G.D. / Pitts, W.J. / Kempson, J. / ...Authors: Kumar, S.R. / Dudhgoankar, S. / Santella, J.B. / Paidi, V.R.R. / Nair, S. / Sistla, R. / Wu, H. / Gardner, D.S. / Stachura, S. / Cavallaro, C.L. / Brown, G.D. / Pitts, W.J. / Kempson, J. / Tebben, A.J. / Tokarski, J.S. / Zhu, X. / Carman, J.A. / Foster, K. / Caceres Cortes, J. / Everlof, G. / Galella, M.A. / Sarjeant, A. / Holloway, D.A. / Fan, L. / Li, X. / Chaudhry, C. / Locke, G. / Chimalakondra, A. / Mariappan, T.T. / Ruepp, S. / Elzinga, P.A. / Saxena, A. / Xie, D. / Kiefer, S.E. / Yan, C. / Newitt, J.A. / Ghosh, K. / Anumula, R.K. / Sack, J.S. / Tino, J.A. / Carter, P.H. / Hynes, J. / Duncia, J.V.
History
DepositionApr 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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


Theoretical massNumber of molelcules
Total (without water)139,56116
Polymers137,0904
Non-polymers2,47012
Water1,06359
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7943
Polymers34,2731
Non-polymers5222
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)34,8904
Polymers34,2731
Non-polymers6183
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)34,9865
Polymers34,2731
Non-polymers7144
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)34,8904
Polymers34,2731
Non-polymers6183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.286, 140.394, 85.915
Angle α, β, γ (deg.)90.00, 126.60, 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: 34272.566 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN
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


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-ZVA / (6M)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-4-[(propan-2-yl)amino]pyridine-3-carboxamide


Mass: 425.459 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H24FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.39 Å3/Da / Density % sol: 48.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 2.6 to 2.9 M ammonium sulphate in 25 mM HEPES pH 6.4 to 7.5 at 293K
PH range: 6.4-7.5

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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: RAYONIX MX-300 / Detector: CCD / Date: Mar 3, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.76→50 Å / Num. obs: 33116 / % possible obs: 99.8 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.101 / Net I/σ(I): 8.1
Reflection shellResolution: 2.76→2.86 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.551 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 3359 / % possible all: 99.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.11.1refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.76→36.68 Å / Cor.coef. Fo:Fc: 0.875 / Cor.coef. Fo:Fc free: 0.852 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.337
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1676 5.06 %RANDOM
Rwork0.195 ---
obs0.197 33104 98.9 %-
Displacement parametersBiso mean: 59.07 Å2
Baniso -1Baniso -2Baniso -3
1--7.3725 Å20 Å2-16.1646 Å2
2--27.5121 Å20 Å2
3----20.1396 Å2
Refine analyzeLuzzati coordinate error obs: 0.341 Å
Refinement stepCycle: LAST / Resolution: 2.76→36.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8661 0 164 59 8884
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018967HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1712186HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3025SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes225HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1398HARMONIC5
X-RAY DIFFRACTIONt_it8967HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.62
X-RAY DIFFRACTIONt_other_torsion20.2
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1205SEMIHARMONIC5
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_contact10415SEMIHARMONIC4
LS refinement shellResolution: 2.76→2.83 Å
RfactorNum. reflection% reflection
Rfree0.2872 122 4.68 %
Rwork0.24 2485 -
obs--98.85 %

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