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- PDB-8v2f: Crystal structure of IRAK4 kinase domain with compound 9 -

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Basic information

Entry
Database: PDB / ID: 8v2f
TitleCrystal structure of IRAK4 kinase domain with compound 9
ComponentsInterleukin-1 receptor-associated kinase 4
KeywordsIMMUNE SYSTEM / Kinase important for immune response. ProTAC design
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 / 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 / interleukin-33-mediated signaling pathway / neutrophil migration / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / interleukin-1-mediated signaling pathway / extrinsic component of plasma membrane / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / JNK cascade / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / lipopolysaccharide-mediated signaling pathway / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / kinase activity / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of canonical NF-kappaB signal transduction / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / 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
: / Interleukin-1 receptor-associated kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsWeiss, M.M. / Zheng, X. / Browne, C.M. / Campbell, V. / Chen, D. / Enerson, B. / Fei, X. / Huang, X. / Klaus, C.R. / Li, H. ...Weiss, M.M. / Zheng, X. / Browne, C.M. / Campbell, V. / Chen, D. / Enerson, B. / Fei, X. / Huang, X. / Klaus, C.R. / Li, H. / Mayo, M. / McDonald, A.A. / Paul, A. / Sharma, K. / Shi, Y. / Slavin, A. / Walter, D.M. / Yuan, K. / Zhang, Y. / Zhu, X. / Kelleher, J. / Ji, N. / Walker, D. / Mainolfi, N.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.
Authors: Weiss, M.M. / Zheng, X. / Ji, N. / Browne, C.M. / Campbell, V. / Chen, D. / Enerson, B. / Fei, X. / Huang, X. / Klaus, C.R. / Li, H. / Mayo, M. / McDonald, A.A. / Paul, A. / Rong, H. / ...Authors: Weiss, M.M. / Zheng, X. / Ji, N. / Browne, C.M. / Campbell, V. / Chen, D. / Enerson, B. / Fei, X. / Huang, X. / Klaus, C.R. / Li, H. / Mayo, M. / McDonald, A.A. / Paul, A. / Rong, H. / Sharma, K. / Shi, Y. / Slavin, A. / Walther, D.M. / Yuan, K. / Zhang, Y. / Zhu, X. / Kelleher, J. / Walker, D. / Mainolfi, N.
History
DepositionNov 22, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 24, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 13, 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)151,37217
Polymers148,8074
Non-polymers2,56513
Water11,151619
1
A: Interleukin-1 receptor-associated kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8985
Polymers37,2021
Non-polymers6964
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)37,8985
Polymers37,2021
Non-polymers6964
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)37,8064
Polymers37,2021
Non-polymers6043
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)37,7703
Polymers37,2021
Non-polymers5692
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)142.870, 140.680, 89.020
Angle α, β, γ (deg.)90.00, 124.00, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-715-

HOH

21D-606-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
44
55
66
/ 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: 37201.680 Da / Num. of mol.: 4 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Plasmid: pFastbac1 / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-YJU / N-{2-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide


Mass: 476.491 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H27F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 619 / 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: 2.49 Å3/Da / Density % sol: 50.64 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 1.8M ammonium citrate, 1.75mM compound (1.8% DMSO)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97915 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.09→49.14 Å / Num. obs: 85963 / % possible obs: 99.86 % / Redundancy: 6.8 % / Biso Wilson estimate: 35.99 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.1389 / Rpim(I) all: 0.0578 / Rrim(I) all: 0.1507 / Χ2: 1.04 / Net I/σ(I): 13.07
Reflection shellResolution: 2.09→2.165 Å / Redundancy: 7 % / Rmerge(I) obs: 1.17 / Mean I/σ(I) obs: 2.35 / Num. unique obs: 8596 / CC1/2: 0.668 / CC star: 0.895 / Rpim(I) all: 0.477 / Rrim(I) all: 1.265 / % possible all: 99.95

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→49.14 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.951 / SU B: 4.519 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.179 / ESU R Free: 0.156 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20754 4334 5 %RANDOM
Rwork0.16814 ---
obs0.17014 81617 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.936 Å2
Baniso -1Baniso -2Baniso -3
1-0.94 Å2-0 Å20.83 Å2
2---3.12 Å2-0 Å2
3---0.56 Å2
Refinement stepCycle: 1 / Resolution: 2.09→49.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9397 0 175 619 10191
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0139785
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179040
X-RAY DIFFRACTIONr_angle_refined_deg1.5891.66313242
X-RAY DIFFRACTIONr_angle_other_deg1.341.59421083
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.30451202
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.43124.153484
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.026151759
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.4281540
X-RAY DIFFRACTIONr_chiral_restr0.0740.21282
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0210755
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021861
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.1464.3574781
X-RAY DIFFRACTIONr_mcbond_other4.1464.3564780
X-RAY DIFFRACTIONr_mcangle_it6.1176.5085968
X-RAY DIFFRACTIONr_mcangle_other6.1166.5095969
X-RAY DIFFRACTIONr_scbond_it5.435.0035004
X-RAY DIFFRACTIONr_scbond_other5.435.0045005
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.2677.2397267
X-RAY DIFFRACTIONr_long_range_B_refined10.80852.05110871
X-RAY DIFFRACTIONr_long_range_B_other10.81951.82710738
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A9173
12B9173
21A9176
22C9176
31A9186
32D9186
41B9239
42C9239
51B9125
52D9125
61C9085
62D9085
LS refinement shellResolution: 2.09→2.144 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 303 -
Rwork0.277 6002 -
obs--99.95 %

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