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- PDB-6sze: RIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazol... -

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Basic information

Entry
Database: PDB / ID: 6sze
TitleRIP2 Kinase Catalytic Domain complex with 5-Amino-1-Phenylpyrazole-4-Carboxamide.
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTRANSFERASE / Fragment Based Drug Design (FBDD) / Receptor interacting protein 2 kinase / RIPK2 / RIP2K / RIP2 / Structure based drug design (SBDD)
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 / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / immature T cell proliferation in thymus / caspase binding / 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 / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / immature T cell proliferation in thymus / caspase binding / xenophagy / LIM domain binding / 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 / CD4-positive, alpha-beta T cell proliferation / cellular response to peptidoglycan / JUN kinase kinase kinase activity / 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 peptidyl-tyrosine phosphorylation / toll-like receptor 4 signaling pathway / positive regulation of macrophage cytokine production / 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 / ERK1 and ERK2 cascade / JNK cascade / positive regulation of interleukin-12 production / signaling adaptor activity / positive regulation of interleukin-2 production / response to interleukin-1 / positive regulation of interferon-beta production / p75NTR recruits signalling complexes / lipopolysaccharide-mediated signaling pathway / positive regulation of protein ubiquitination / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of interleukin-1 beta production / non-membrane spanning protein tyrosine kinase activity / activated TAK1 mediates p38 MAPK activation / non-specific protein-tyrosine kinase / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / protein homooligomerization / positive regulation of JNK cascade / positive regulation of interleukin-6 production / positive regulation of type II interferon production / cytokine-mediated signaling pathway / 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 / 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 bacterium / defense response to Gram-positive 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 / 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 / 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
5-Amino-1-Phenylpyrazole-4-Carboxamide / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.94 Å
AuthorsConvery, M.A. / Charnley, A.K. / Shewchuk, L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.
Authors: Haffner, C.D. / Charnley, A.K. / Aquino, C.J. / Casillas, L. / Convery, M.A. / Cox, J.A. / Elban, M.A. / Goodwin, N.C. / Gough, P.J. / Haile, P.A. / Hughes, T.V. / Knapp-Reed, B. / ...Authors: Haffner, C.D. / Charnley, A.K. / Aquino, C.J. / Casillas, L. / Convery, M.A. / Cox, J.A. / Elban, M.A. / Goodwin, N.C. / Gough, P.J. / Haile, P.A. / Hughes, T.V. / Knapp-Reed, B. / Kreatsoulas, C. / Lakdawala, A.S. / Li, H. / Lian, Y. / Lipshutz, D. / Mehlmann, J.F. / Ouellette, M. / Romano, J. / Shewchuk, L. / Shu, A. / Votta, B.J. / Zhou, H. / Bertin, J. / Marquis, R.W.
History
DepositionOct 2, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)71,8105
Polymers71,3662
Non-polymers4453
Water2,846158
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3680 Å2
ΔGint-34 kcal/mol
Surface area24380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)131.660, 131.660, 107.084
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Receptor-interacting serine/threonine-protein kinase 2


Mass: 35682.977 Da / Num. of mol.: 2
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 serine/threonine protein kinase
#2: Chemical ChemComp-M2B / 5-Amino-1-Phenylpyrazole-4-Carboxamide


Mass: 202.213 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H10N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 158 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.75 Å3/Da / Density % sol: 67.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100mM buffer (Mes or Hepes pH6.8-7.5), 12-28% PEG 400, 50-250mM CaCl2, 0-200mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Sep 9, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.94→23.67 Å / Num. obs: 22644 / % possible obs: 98.2 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 12.8
Reflection shellResolution: 2.94→3.1 Å / Rmerge(I) obs: 0.397 / Mean I/σ(I) obs: 4.1 / Num. unique obs: 3264 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.94→20 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.9 / SU B: 12.353 / SU ML: 0.231 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.68 / ESU R Free: 0.329 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2341 1154 5.1 %RANDOM
Rwork0.1761 ---
obs0.1791 21429 97.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 160.66 Å2 / Biso mean: 46.64 Å2 / Biso min: 1 Å2
Baniso -1Baniso -2Baniso -3
1-1.12 Å20.56 Å20 Å2
2--1.12 Å2-0 Å2
3----3.64 Å2
Refinement stepCycle: final / Resolution: 2.94→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4449 0 31 158 4638
Biso mean--32.91 32.72 -
Num. residues----550
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194607
X-RAY DIFFRACTIONr_angle_refined_deg1.5461.976267
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.1085543
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.1323.476210
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.15615769
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.0451530
X-RAY DIFFRACTIONr_chiral_restr0.110.2700
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213526
LS refinement shellResolution: 2.94→3.015 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 74 -
Rwork0.276 1539 -
all-1613 -
obs--97.64 %

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