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- PDB-7c2w: Crystal Structure of IRAK4 kinase in complex with a small molecul... -

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Basic information

Entry
Database: PDB / ID: 7c2w
TitleCrystal Structure of IRAK4 kinase in complex with a small molecule inhibitor
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / IRAK4 / Inhibitor / CA-4948 / Kinase / CELL CYCLE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / 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 ...MyD88 dependent cascade initiated on endosome / IRAK4 deficiency (TLR5) / 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 / 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 / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / PIP3 activates AKT signaling / kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cellular response to lipopolysaccharide / 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 / cell surface / magnesium ion binding / 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 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-FJ9 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsKrishnamurthy, N.R. / Anirudha, L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies.
Authors: Gummadi, V.R. / Boruah, A. / Ainan, B.R. / Vare, B.R. / Manda, S. / Gondle, H.P. / Kumar, S.N. / Mukherjee, S. / Gore, S.T. / Krishnamurthy, N.R. / Marappan, S. / Nayak, S.S. / Nellore, K. / ...Authors: Gummadi, V.R. / Boruah, A. / Ainan, B.R. / Vare, B.R. / Manda, S. / Gondle, H.P. / Kumar, S.N. / Mukherjee, S. / Gore, S.T. / Krishnamurthy, N.R. / Marappan, S. / Nayak, S.S. / Nellore, K. / Balasubramanian, W.R. / Bhumireddy, A. / Giri, S. / Gopinath, S. / Samiulla, D.S. / Daginakatte, G. / Basavaraju, A. / Chelur, S. / Eswarappa, R. / Belliappa, C. / Subramanya, H.S. / Booher, R.N. / Ramachandra, M. / Samajdar, S.
History
DepositionMay 9, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)135,2738
Polymers133,6674
Non-polymers1,6064
Water2,954164
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-24 kcal/mol
Surface area52580 Å2
Unit cell
Length a, b, c (Å)137.630, 140.802, 86.496
Angle α, β, γ (deg.)90.000, 127.640, 90.000
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: 33416.766 Da / Num. of mol.: 4
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-FJ9 / N-(2-morpholin-4-yl-1,3-benzoxazol-6-yl)-6-pyridin-4-yl-pyridine-2-carboxamide


Mass: 401.418 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H19N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / 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: 2.49 Å3/Da / Density % sol: 50.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.4 / Details: 0.1 M sodium acetate pH 5.4, 2.3 M sodium malonate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-002+ / Wavelength: 1.5 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: May 9, 2010
RadiationMonochromator: Ni Filter / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 3.14→100 Å / Num. obs: 21131 / % possible obs: 89.9 % / Redundancy: 2.4 % / CC1/2: 0.76 / Rmerge(I) obs: 0.095 / Net I/σ(I): 2.4
Reflection shellResolution: 3.14→3.21 Å / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2073 / CC1/2: 0.75 / % possible all: 86.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0001refinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NRU

2nru


Resolution: 3.2→29.62 Å / Cor.coef. Fo:Fc: 0.851 / Cor.coef. Fo:Fc free: 0.699 / SU B: 38.307 / SU ML: 0.641 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.873 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.355 977 5.1 %RANDOM
Rwork0.2614 ---
obs0.2662 18229 89.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 61.32 Å2 / Biso mean: 34.886 Å2 / Biso min: 12.23 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å20 Å2-0.16 Å2
2--0.01 Å20 Å2
3----0.01 Å2
Refinement stepCycle: final / Resolution: 3.2→29.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9323 0 120 164 9607
Biso mean--36.09 29.51 -
Num. residues----1181
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0229619
X-RAY DIFFRACTIONr_bond_other_d0.0010.028598
X-RAY DIFFRACTIONr_angle_refined_deg1.1341.98512994
X-RAY DIFFRACTIONr_angle_other_deg0.718320126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.94751177
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.01325.446448
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.45215.0341745
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4241540
X-RAY DIFFRACTIONr_chiral_restr0.0550.21438
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0210599
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021821
X-RAY DIFFRACTIONr_nbd_refined0.2130.22828
X-RAY DIFFRACTIONr_nbd_other0.170.210018
X-RAY DIFFRACTIONr_nbtor_other0.0810.25363
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1890.2458
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0740.25
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1660.260
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1970.2170
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3930.218
LS refinement shellResolution: 3.2→3.282 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.422 64
Rwork0.29 1310
all-1374

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