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- PDB-5w5j: Identification of potent and selective RIPK2 inhibitors for the t... -

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Basic information

Entry
Database: PDB / ID: 5w5j
TitleIdentification of potent and selective RIPK2 inhibitors for the treatment of inflammatory diseases
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Complex / Kinase / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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 / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / caspase binding / 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 / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / caspase binding / 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 / JUN kinase kinase kinase activity / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of macrophage cytokine production / positive regulation of peptidyl-tyrosine phosphorylation / toll-like receptor 4 signaling pathway / 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 / ERK1 and ERK2 cascade / positive regulation of interleukin-12 production / positive regulation of interleukin-2 production / p75NTR recruits signalling complexes / response to interleukin-1 / 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 / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / cytokine-mediated signaling pathway / protein homooligomerization / positive regulation of interleukin-6 production / Interleukin-1 signaling / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / Downstream TCR signaling / T cell receptor signaling pathway / vesicle / adaptive immune response / cytoskeleton / positive regulation of canonical NF-kappaB signal transduction / 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 / identical protein binding / plasma membrane / cytosol / cytoplasm
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 / Transferase(Phosphotransferase) domain 1 ...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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-9WS / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsKreusch, A. / Spraggon, G.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases.
Authors: He, X. / Da Ros, S. / Nelson, J. / Zhu, X. / Jiang, T. / Okram, B. / Jiang, S. / Michellys, P.Y. / Iskandar, M. / Espinola, S. / Jia, Y. / Bursulaya, B. / Kreusch, A. / Gao, M.Y. / Spraggon, ...Authors: He, X. / Da Ros, S. / Nelson, J. / Zhu, X. / Jiang, T. / Okram, B. / Jiang, S. / Michellys, P.Y. / Iskandar, M. / Espinola, S. / Jia, Y. / Bursulaya, B. / Kreusch, A. / Gao, M.Y. / Spraggon, G. / Baaten, J. / Clemmer, L. / Meeusen, S. / Huang, D. / Hill, R. / Nguyen-Tran, V. / Fathman, J. / Liu, B. / Tuntland, T. / Gordon, P. / Hollenbeck, T. / Ng, K. / Shi, J. / Bordone, L. / Liu, H.
History
DepositionJun 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)72,0797
Polymers71,2482
Non-polymers8325
Water45025
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3540 Å2
ΔGint-50 kcal/mol
Surface area23110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.213, 92.264, 126.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 35623.910 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: unidentified baculovirus / Strain (production host): sf9
References: UniProt: O43353, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9WS / N-(2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide


Mass: 271.702 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10ClN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / Source method: isolated from a natural source / Formula: H2O

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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: 48.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 1.6M ammonium sulfate, 0.1M citric acid pH 5.0 / PH range: 4.0-5.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.85→46 Å / Num. obs: 16533 / % possible obs: 99.8 % / Redundancy: 3.6 % / Biso Wilson estimate: 83.54 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 5.3
Reflection shellResolution: 2.85→2.95 Å / Rmerge(I) obs: 0.65 / Num. unique obs: 1628 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished in-house structure

Resolution: 2.85→46 Å / Cor.coef. Fo:Fc: 0.9131 / Cor.coef. Fo:Fc free: 0.8685 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 3.171 / SU Rfree Blow DPI: 0.373 / SU Rfree Cruickshank DPI: 0.379
RfactorNum. reflection% reflectionSelection details
Rfree0.2681 812 4.91 %RANDOM
Rwork0.2171 ---
obs0.2196 16533 99.94 %-
Displacement parametersBiso mean: 72.48 Å2
Baniso -1Baniso -2Baniso -3
1-2.1106 Å20 Å20 Å2
2---15.8079 Å20 Å2
3---13.6973 Å2
Refine analyzeLuzzati coordinate error obs: 0.366 Å
Refinement stepCycle: 1 / Resolution: 2.85→46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3996 0 53 25 4074
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014156HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.165678HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1334SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes83HARMONIC2
X-RAY DIFFRACTIONt_gen_planes601HARMONIC5
X-RAY DIFFRACTIONt_it4156HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.65
X-RAY DIFFRACTIONt_other_torsion20.86
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion558SEMIHARMONIC5
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_contact4622SEMIHARMONIC4
LS refinement shellResolution: 2.85→3.05 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.3421 148 5.02 %
Rwork0.2276 2803 -
all0.2333 2951 -
obs--99.94 %

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