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- PDB-5j7b: The identification and pharmacological characterization of 6-(ter... -

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Basic information

Entry
Database: PDB / ID: 5j7b
TitleThe identification and pharmacological characterization of 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a highly potent and selective inhibitor of RIP2 Kinase, GSK583 complex
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTransferase/Transferase Inhibitor / kinase domain / kinase inhibitor / structure-based drug design / inhibitor selectivity / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / LIM domain binding / xenophagy / CD4-positive, alpha-beta T cell proliferation ...response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / positive regulation of cytokine-mediated signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / LIM domain binding / xenophagy / CD4-positive, alpha-beta T cell proliferation / nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of protein K63-linked ubiquitination / positive regulation of stress-activated MAPK cascade / cellular response to muramyl dipeptide / CARD domain binding / positive regulation of immature T cell proliferation in thymus / caspase binding / JUN kinase kinase kinase activity / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / activation of cysteine-type endopeptidase activity / nucleotide-binding oligomerization domain containing 2 signaling pathway / positive regulation of macrophage cytokine production / toll-like receptor 4 signaling pathway / response to exogenous dsRNA / cellular response to lipoteichoic acid / canonical NF-kappaB signal transduction / positive regulation of interferon-alpha production / signaling adaptor activity / stress-activated MAPK cascade / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / p75NTR recruits signalling complexes / ERK1 and ERK2 cascade / positive regulation of interleukin-12 production / positive regulation of interleukin-2 production / positive regulation of interferon-beta production / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / activated TAK1 mediates p38 MAPK activation / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / TAK1-dependent IKK and NF-kappa-B activation / non-membrane spanning protein tyrosine kinase activity / NOD1/2 Signaling Pathway / protein homooligomerization / cytokine-mediated signaling pathway / Interleukin-1 signaling / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of type II interferon production / Ovarian tumor domain proteases / Downstream TCR signaling / positive regulation of protein binding / positive regulation of peptidyl-serine phosphorylation / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / positive regulation of canonical NF-kappaB signal transduction / adaptive immune response / vesicle / positive regulation of ERK1 and ERK2 cascade / cytoskeleton / non-specific serine/threonine protein kinase / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / positive regulation of apoptotic process / phosphorylation / innate immune response / protein serine kinase activity / signaling receptor binding / 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 / cytoplasm / cytosol
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-6GD / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.53 Å
AuthorsConvery, M.A. / Casillas, L.N. / Haile, P.A. / Votta, B.J. / Lakdawala, A.S.
CitationJournal: J.Med.Chem. / Year: 2016
Title: The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.
Authors: Haile, P.A. / Votta, B.J. / Marquis, R.W. / Bury, M.J. / Mehlmann, J.F. / Singhaus, R. / Charnley, A.K. / Lakdawala, A.S. / Convery, M.A. / Lipshutz, D.B. / Desai, B.M. / Swift, B. / ...Authors: Haile, P.A. / Votta, B.J. / Marquis, R.W. / Bury, M.J. / Mehlmann, J.F. / Singhaus, R. / Charnley, A.K. / Lakdawala, A.S. / Convery, M.A. / Lipshutz, D.B. / Desai, B.M. / Swift, B. / Capriotti, C.A. / Berger, S.B. / Mahajan, M.K. / Reilly, M.A. / Rivera, E.J. / Sun, H.H. / Nagilla, R. / Beal, A.M. / Finger, J.N. / Cook, M.N. / King, B.W. / Ouellette, M.T. / Totoritis, R.D. / Pierdomenico, M. / Negroni, A. / Stronati, L. / Cucchiara, S. / Ziokowski, B. / Vossenkamper, A. / MacDonald, T.T. / Gough, P.J. / Bertin, J. / Casillas, L.N.
History
DepositionApr 6, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / diffrn_source / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation

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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)76,0094
Polymers75,2122
Non-polymers7972
Water4,630257
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3730 Å2
ΔGint-26 kcal/mol
Surface area24800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)132.381, 132.381, 107.280
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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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: 37605.980 Da / Num. of mol.: 2 / Fragment: UNP residues 1-310
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-6GD / 6-(tert-butylsulfonyl)-N-(5-fluoro-2H-indazol-3-yl)quinolin-4-amine


Mass: 398.454 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19FN4O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 3.61 Å3/Da / Density % sol: 65.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7
Details: 100mM Mes pH7, 12% PEG 400, 250mM CaCl2. Crystals soaked in compound for 2 hours.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.95 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 20, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95 Å / Relative weight: 1
ReflectionResolution: 2.53→78.33 Å / Num. obs: 36582 / % possible obs: 99.9 % / Redundancy: 6 % / Rmerge(I) obs: 0.095 / Net I/σ(I): 12.9
Reflection shellResolution: 2.53→2.67 Å / Redundancy: 6 % / Rmerge(I) obs: 0.385 / Mean I/σ(I) obs: 4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5ar4

5ar4


Resolution: 2.53→20 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.931 / SU B: 7.392 / SU ML: 0.161 / Cross valid method: THROUGHOUT / ESU R: 0.257 / ESU R Free: 0.223
RfactorNum. reflection% reflectionSelection details
Rfree0.23255 1825 5 %RANDOM
Rwork0.17973 ---
obs0.18235 34651 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 70.473 Å2
Baniso -1Baniso -2Baniso -3
1-1.14 Å20.57 Å20 Å2
2--1.14 Å2-0 Å2
3----3.71 Å2
Refinement stepCycle: 1 / Resolution: 2.53→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4470 0 56 257 4783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0194648
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2981.9556337
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.0995551
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.15923.43207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.35815762
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.1391530
X-RAY DIFFRACTIONr_chiral_restr0.1020.2704
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213506
X-RAY DIFFRACTIONr_gen_planes_other
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_it6.1989.4742225
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it9.32521.2252769
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it6.979.4692420
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined12.85948.9597122
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.53→2.595 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.317 122 -
Rwork0.259 2536 -
obs--100 %

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