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- PDB-5ar7: RIP2 Kinase Catalytic Domain (1 - 310) complex with Biaryl Urea -

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Basic information

Entry
Database: PDB / ID: 5ar7
TitleRIP2 Kinase Catalytic Domain (1 - 310) complex with Biaryl Urea
ComponentsRECEPTOR-INTERACTING SERINE/THREONINE-PROTEIN KINASE 2
KeywordsTRANSFERASE / KINASE DOMAIN / KINASE INHIBITOR / STRUCTURE-BASED DRUG DESIGN / INHIBITOR SELECTIVITY
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 / cellular response to muramyl dipeptide / caspase binding / positive regulation of immature T cell proliferation in thymus / CARD domain 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 / positive regulation of interferon-alpha production / canonical NF-kappaB signal transduction / signaling adaptor activity / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / p75NTR recruits signalling complexes / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / positive regulation of interleukin-12 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 type II interferon production / positive regulation of peptidyl-tyrosine phosphorylation / 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 / signaling receptor binding / protein serine kinase activity / innate immune response / 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 / 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-SR8 / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 Å
AuthorsCharnley, A.K. / Convery, M.A. / Lakdawala Shah, A. / Jones, E. / Hardwicke, P. / Bridges, A. / Votta, B.J. / Gough, P.J. / Marquis, R.W. / Bertin, J. / Casillas, L.
CitationJournal: Bioorg.Med.Chem. / Year: 2015
Title: Crystal Structures of Human Rip2 Kinase Catalytic Domain Complexed with ATP-Competitive Inhibitors: Foundations for Understanding Inhibitor Selectivity.
Authors: Charnley, A.K. / Convery, M.A. / Lakdawala Shah, A. / Jones, E. / Hardwicke, P. / Bridges, A. / Ouellette, M. / Totoritis, R. / Schwartz, B. / King, B.W. / Wisnoski, D.D. / Kang, J. / Eidam, ...Authors: Charnley, A.K. / Convery, M.A. / Lakdawala Shah, A. / Jones, E. / Hardwicke, P. / Bridges, A. / Ouellette, M. / Totoritis, R. / Schwartz, B. / King, B.W. / Wisnoski, D.D. / Kang, J. / Eidam, P.M. / Votta, B.J. / Gough, P.J. / Marquis, R.W. / Bertin, J. / Casillas, L.
History
DepositionSep 24, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 21, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)75,9174
Polymers75,2122
Non-polymers7052
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3660 Å2
ΔGint-27.2 kcal/mol
Surface area24760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.600, 131.600, 107.540
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 / RECEPTOR-INTERACTING SERINE THREONINE-PROTEIN KINASE 2


Mass: 37605.980 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, UNP RESIDUES 1-310
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O43353, non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SR8 / 1-(5-TERT-BUTYL-1,2-OXAZOL-3-YL)-3-(4-PYRIDIN-4-YLOXYPHENYL)UREA


Mass: 352.387 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20N4O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 3.57 Å3/Da / Density % sol: 65.59 % / Description: NONE
Crystal growpH: 6.5 / Details: 30% PEG300, 0.1M MES PH6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.71→80 Å / Num. obs: 29605 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Biso Wilson estimate: 64.96 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 10.2
Reflection shellResolution: 2.71→2.86 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 3.1 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 5AR4

5ar4


Resolution: 2.71→34.13 Å / Cor.coef. Fo:Fc: 0.9368 / Cor.coef. Fo:Fc free: 0.9104 / SU R Cruickshank DPI: 0.336 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.344 / SU Rfree Blow DPI: 0.245 / SU Rfree Cruickshank DPI: 0.246
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2252 1501 5.08 %RANDOM
Rwork0.1814 ---
obs0.1836 29559 99.93 %-
Displacement parametersBiso mean: 57.11 Å2
Baniso -1Baniso -2Baniso -3
1--5.1978 Å20 Å20 Å2
2---5.1978 Å20 Å2
3---10.3955 Å2
Refine analyzeLuzzati coordinate error obs: 0.314 Å
Refinement stepCycle: LAST / Resolution: 2.71→34.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4517 0 52 234 4803
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014708HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.16407HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1600SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes106HARMONIC2
X-RAY DIFFRACTIONt_gen_planes672HARMONIC5
X-RAY DIFFRACTIONt_it4708HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion18.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion608SEMIHARMONIC5
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_contact5388SEMIHARMONIC4
LS refinement shellResolution: 2.71→2.81 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3074 157 5.47 %
Rwork0.2302 2715 -
all0.2344 2872 -
obs--99.93 %

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