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- PDB-7c2v: Crystal Structure of IRAK4 kinase in complex with the inhibitor C... -

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Basic information

Entry
Database: PDB / ID: 7c2v
TitleCrystal Structure of IRAK4 kinase in complex with the inhibitor CA-4948
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


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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FJ0 / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsKrishnamurthy, N.R. / Robert, B.
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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)137,3948
Polymers135,4284
Non-polymers1,9664
Water7,242402
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-24 kcal/mol
Surface area49650 Å2
Unit cell
Length a, b, c (Å)142.759, 138.589, 87.359
Angle α, β, γ (deg.)90.000, 124.500, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: _

Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111THRTHRAA163 - 4593 - 299
221THRTHRBB163 - 4593 - 299
132ARGARGAA164 - 4594 - 299
242ARGARGCC164 - 4594 - 299
153ARGARGAA164 - 4594 - 299
263ARGARGDD164 - 4594 - 299
174ARGARGBB164 - 4594 - 299
284ARGARGCC164 - 4594 - 299
195ARGARGBB164 - 4594 - 299
2105ARGARGDD164 - 4594 - 299
1116ARGARGCC164 - 4594 - 299
2126ARGARGDD164 - 4594 - 299

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Interleukin-1 receptor-associated kinase 4 / IRAK-4 / Renal carcinoma antigen NY-REN-64


Mass: 33857.066 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-FJ0 / 2-(2-methylpyridin-4-yl)-N-[2-morpholin-4-yl-5-[(3R)-3-oxidanylpyrrolidin-1-yl]-[1,3]oxazolo[4,5-b]pyridin-6-yl]-1,3-oxazole-4-carboxamide


Mass: 491.499 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H25N7O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / 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: 2.54 Å3/Da / Density % sol: 51.5 %
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: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 1 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Dec 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.44→30 Å / Num. obs: 51404 / % possible obs: 98.9 % / Redundancy: 2.8 % / CC1/2: 0.8 / Rmerge(I) obs: 0.133 / Net I/σ(I): 6.2
Reflection shellResolution: 2.44→2.57 Å / Rmerge(I) obs: 0.7 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 7467 / CC1/2: 0.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OIB

2oib


Resolution: 2.44→30 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.909 / SU B: 10.71 / SU ML: 0.229 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.473 / ESU R Free: 0.281 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 2535 4.9 %RANDOM
Rwork0.1955 ---
obs0.1983 48865 98.8 %-
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: 206.83 Å2 / Biso mean: 64.799 Å2 / Biso min: 25.09 Å2
Baniso -1Baniso -2Baniso -3
1-1.45 Å2-0 Å21.59 Å2
2---3.9 Å20 Å2
3---0.13 Å2
Refinement stepCycle: final / Resolution: 2.44→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8976 0 144 402 9522
Biso mean--54.29 55.2 -
Num. residues----1143
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0199308
X-RAY DIFFRACTIONr_bond_other_d0.0020.028538
X-RAY DIFFRACTIONr_angle_refined_deg1.5221.99412580
X-RAY DIFFRACTIONr_angle_other_deg1.03319912
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7151135
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.95725.316427
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.987151664
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6491540
X-RAY DIFFRACTIONr_chiral_restr0.0920.21391
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0210207
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021749
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A176680.07
12B176680.07
21A177920.07
22C177920.07
31A181280.08
32D181280.08
41B173020.08
42C173020.08
51B176560.07
52D176560.07
61C177940.08
62D177940.08
LS refinement shellResolution: 2.44→2.503 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 189 -
Rwork0.304 3575 -
all-3764 -
obs--98.77 %

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