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- PDB-9f3v: RIP2K kinase domain dimer with bound compound 37 (N399), a speifi... -

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Basic information

Entry
Database: PDB / ID: 9f3v
TitleRIP2K kinase domain dimer with bound compound 37 (N399), a speific NOD1 pathway inhibitor
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsIMMUNE SYSTEM / kinase
Function / homology
Function and homology information


response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / positive regulation of cytokine-mediated signaling pathway / caspase binding / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / xenophagy / LIM domain binding ...response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / positive regulation of cytokine-mediated signaling pathway / caspase binding / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / xenophagy / LIM domain binding / positive regulation of protein K63-linked ubiquitination / nucleotide-binding oligomerization domain containing 1 signaling pathway / cellular response to muramyl dipeptide / positive regulation of stress-activated MAPK cascade / CARD domain binding / positive regulation of immature T cell proliferation in thymus / CD4-positive, alpha-beta T cell proliferation / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / JUN kinase kinase kinase activity / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of macrophage cytokine production / toll-like receptor 4 signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / response to exogenous dsRNA / cellular response to lipoteichoic acid / positive regulation of interferon-alpha production / canonical NF-kappaB signal transduction / stress-activated MAPK cascade / positive regulation of chemokine production / JNK cascade / signaling adaptor activity / positive regulation of interleukin-12 production / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / response to interleukin-1 / p75NTR recruits signalling complexes / positive regulation of interferon-beta production / lipopolysaccharide-mediated signaling pathway / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / activated TAK1 mediates p38 MAPK activation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / positive regulation of JNK cascade / TAK1-dependent IKK and NF-kappa-B activation / NOD1/2 Signaling Pathway / cytokine-mediated signaling pathway / protein homooligomerization / positive regulation of interleukin-6 production / positive regulation of type II interferon production / Interleukin-1 signaling / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / Downstream TCR signaling / T cell receptor signaling pathway / vesicle / adaptive immune response / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of canonical NF-kappaB signal transduction / cytoskeleton / 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 / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / defense response to Gram-positive bacterium / defense response to bacterium / positive regulation of apoptotic process / inflammatory response / signaling receptor binding / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / ATP binding
Similarity search - Function
Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site ...Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / : / Death-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.943 Å
AuthorsCusack, S. / Huard, K. / Pellegrini, E.
Funding support France, 1items
OrganizationGrant numberCountry
Other governmentEuropean Molecular Biology Laboratory France
CitationJournal: J.Med.Chem. / Year: 2024
Title: 4-Anilinoquinazoline Derivatives as the First Potent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range.
Authors: Barczyk, A. / Six, P. / Rivoal, M. / Devos, C. / Dezitter, X. / Cornu-Choi, M.J. / Huard, K. / Pellegrini, E. / Cusack, S. / Dubuquoy, L. / Millet, R. / Leleu-Chavain, N.
History
DepositionApr 26, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor-interacting serine/threonine-protein kinase 2
B: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,2194
Polymers73,2882
Non-polymers9312
Water2,324129
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3150 Å2
ΔGint-13 kcal/mol
Surface area25420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.824, 90.750, 137.976
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: LEU / End label comp-ID: LEU / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 9 - 314 / Label seq-ID: 13 - 318

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

#1: Protein Receptor-interacting serine/threonine-protein kinase 2 / CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ...CARD-containing interleukin-1 beta-converting enzyme-associated kinase / CARD-containing IL-1 beta ICE-kinase / RIP-like-interacting CLARP kinase / Receptor-interacting protein 2 / RIP-2 / Tyrosine-protein kinase RIPK2


Mass: 36644.156 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Expressed as a cleavable MBP fusion protein / Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-A1H90 / N-[2,4-bis(chloranyl)-5-methoxy-phenyl]-7-[2-(diethylamino)ethoxy]-6-methoxy-quinazolin-4-amine


Mass: 465.373 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26Cl2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.34 Å3/Da / Density % sol: 47.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Compound 37, in powder form was solubilized in DMSO at 5 mM concentration. One aliquot of protein at 1.14 mg/ml was thawed and mixed with 50 microM inhibitor and kept on ice for 10 minutes. ...Details: Compound 37, in powder form was solubilized in DMSO at 5 mM concentration. One aliquot of protein at 1.14 mg/ml was thawed and mixed with 50 microM inhibitor and kept on ice for 10 minutes. The complex was than concentrated to 3.8 mg/ml. solutions containing 3.8 mg/ml of protein-inhibitor complex equilibrated against 0.1 M citric acid and 0.8 M sodium formate at pH 5.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.9655 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9655 Å / Relative weight: 1
ReflectionResolution: 1.943→54.981 Å / Num. obs: 48396 / % possible obs: 96.1 % / Redundancy: 5.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.093 / Rrim(I) all: 0.104 / Net I/σ(I): 8
Reflection shellResolution: 1.943→1.976 Å / Rmerge(I) obs: 2.848 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 2449 / CC1/2: 0.393 / Rrim(I) all: 3.171 / % possible all: 95.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
autoPROCdata reduction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.943→54.981 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.738 / SU ML: 0.171 / Cross valid method: FREE R-VALUE / ESU R: 0.186 / ESU R Free: 0.166
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2564 2454 5.071 %
Rwork0.2203 45942 -
all0.222 --
obs-48396 93.84 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 57.567 Å2
Baniso -1Baniso -2Baniso -3
1--1.722 Å2-0 Å20 Å2
2--3.057 Å2-0 Å2
3----1.336 Å2
Refinement stepCycle: LAST / Resolution: 1.943→54.981 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4504 0 62 129 4695
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0124737
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164515
X-RAY DIFFRACTIONr_angle_refined_deg1.0841.6696446
X-RAY DIFFRACTIONr_angle_other_deg0.371.57910412
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9125551
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.276543
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.33110811
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.67110220
X-RAY DIFFRACTIONr_chiral_restr0.0550.2711
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025441
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021057
X-RAY DIFFRACTIONr_nbd_refined0.2090.2954
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1880.24076
X-RAY DIFFRACTIONr_nbtor_refined0.1790.22303
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0770.22355
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1520.2154
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0440.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1860.217
X-RAY DIFFRACTIONr_nbd_other0.2120.242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1950.210
X-RAY DIFFRACTIONr_mcbond_it3.9135.712213
X-RAY DIFFRACTIONr_mcbond_other3.9135.712213
X-RAY DIFFRACTIONr_mcangle_it5.9910.2332761
X-RAY DIFFRACTIONr_mcangle_other5.98910.2332762
X-RAY DIFFRACTIONr_scbond_it4.176.1672524
X-RAY DIFFRACTIONr_scbond_other4.1696.1672525
X-RAY DIFFRACTIONr_scangle_it6.83211.1273685
X-RAY DIFFRACTIONr_scangle_other6.83111.1273686
X-RAY DIFFRACTIONr_lrange_it9.65156.0595334
X-RAY DIFFRACTIONr_lrange_other9.64355.8485312
X-RAY DIFFRACTIONr_ncsr_local_group_10.1060.058586
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.105990.05008
12AX-RAY DIFFRACTIONLocal ncs0.105990.05008
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.943-1.9940.3941460.40425990.40437520.8220.82673.1610.404
1.994-2.0480.371680.38433830.38336690.6550.68396.78390.387
2.048-2.1080.3771800.38528880.38435670.6920.70286.01070.38
2.108-2.1720.3171740.30832750.30934500.8990.90799.9710.304
2.172-2.2430.2891640.31328700.31133370.9190.90690.920.303
2.243-2.3220.351760.2830470.28432930.8630.89397.87430.259
2.322-2.410.2661620.23829730.23931400.950.95899.84080.219
2.41-2.5080.261390.22628870.22830320.9560.96599.80210.204
2.508-2.6190.2641410.20727560.20928980.960.9799.96550.183
2.619-2.7470.2831080.24523590.24728060.9230.95187.91870.215
2.747-2.8950.2441330.20925210.21126540.9640.9721000.19
2.895-3.070.2761320.21923780.22225120.9480.96999.92040.205
3.07-3.2810.2361120.21522620.21623780.960.97299.83180.211
3.281-3.5430.2181100.21718750.21722230.9680.96689.29370.217
3.543-3.8790.247840.2116110.21220600.9690.97582.28160.217
3.879-4.3350.183920.16816670.16918750.9780.98493.81330.188
4.335-50.208780.15815790.16116680.9740.98699.34050.187
5-6.1110.269660.19513450.19814250.9550.97999.01750.225
6.111-8.5890.228470.19310540.19511280.9690.97897.60640.237
8.589-54.9810.293420.2326130.2366920.9120.95294.65320.279

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