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- PDB-6szj: RIP2 Kinase Catalytic Domain complex with 5amino1tertbutyl3(3meth... -

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Basic information

Entry
Database: PDB / ID: 6szj
TitleRIP2 Kinase Catalytic Domain complex with 5amino1tertbutyl3(3methoxyphenyl)1H pyrazole4carboxamide.
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 / immature T cell proliferation in thymus / caspase binding / positive regulation of T-helper 1 type immune response / CARD domain binding / positive regulation of xenophagy / xenophagy ...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 / caspase binding / positive regulation of T-helper 1 type immune response / CARD domain 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 / 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 / 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 / positive regulation of interferon-alpha production / cellular response to lipoteichoic acid / canonical NF-kappaB signal transduction / lipopolysaccharide-mediated signaling pathway / signaling adaptor activity / stress-activated MAPK cascade / positive regulation of chemokine production / JNK cascade / positive regulation of interleukin-12 production / positive regulation of interleukin-2 production / p75NTR recruits signalling complexes / positive regulation of interferon-beta production / ERK1 and ERK2 cascade / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of interleukin-1 beta production / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein ubiquitination / activated TAK1 mediates p38 MAPK activation / non-specific protein-tyrosine kinase / positive regulation of JNK cascade / non-membrane spanning protein tyrosine kinase activity / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / protein homooligomerization / cytokine-mediated signaling pathway / Interleukin-1 signaling / positive regulation of interleukin-6 production / positive regulation of type II interferon production / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / Ovarian tumor domain proteases / positive regulation of protein binding / Downstream TCR signaling / 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 / vesicle / adaptive immune response / 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 / innate immune response / signaling receptor binding / 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-M5W / 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. / 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 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1May 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)71,9835
Polymers71,3662
Non-polymers6173
Water3,099172
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3790 Å2
ΔGint-33 kcal/mol
Surface area25110 Å2
Unit cell
Length a, b, c (Å)132.182, 132.182, 107.088
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-M5W / 5-amino-1-~{tert}-butyl-3-(3-methoxyphenyl)pyrazole-4-carboxamide


Mass: 288.345 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H20N4O2 / 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.: 172 / 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: 3.78 Å3/Da / Density % sol: 67.5 %
Crystal growTemperature: 298 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: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 10, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.53→40 Å / Num. obs: 36439 / % possible obs: 100 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.058 / Net I/σ(I): 18.45
Reflection shellResolution: 2.53→2.57 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.341 / Mean I/σ(I) obs: 2.27 / Num. unique obs: 1819 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.53→20 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.931 / SU B: 8.96 / SU ML: 0.188 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.264 / ESU R Free: 0.228 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2406 1452 4 %RANDOM
Rwork0.1889 ---
obs0.191 34809 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 191.63 Å2 / Biso mean: 67.729 Å2 / Biso min: 29.92 Å2
Baniso -1Baniso -2Baniso -3
1-1.5 Å20.75 Å20 Å2
2--1.5 Å2-0 Å2
3----4.88 Å2
Refinement stepCycle: final / Resolution: 2.53→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4493 0 43 172 4708
Biso mean--52.28 57.24 -
Num. residues----562
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194664
X-RAY DIFFRACTIONr_angle_refined_deg1.4671.9766357
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.1615557
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.21823.462208
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.02815763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg6.5361530
X-RAY DIFFRACTIONr_chiral_restr0.110.2708
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213584
LS refinement shellResolution: 2.53→2.595 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 102 -
Rwork0.296 2526 -
all-2628 -
obs--99.92 %

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