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- PDB-6s1f: Structure of the kinase domain of human RIPK2 in complex with the... -

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Basic information

Entry
Database: PDB / ID: 6s1f
TitleStructure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP3
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsSIGNALING PROTEIN / RIPK2 CSLP3
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 / caspase binding / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / 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 / caspase binding / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / 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 / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / JUN kinase kinase kinase activity / 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 / positive regulation of interleukin-12 production / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / response to interleukin-1 / p75NTR recruits signalling complexes / 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 / non-specific protein-tyrosine kinase / positive regulation of JNK cascade / TAK1-dependent IKK and NF-kappa-B activation / NOD1/2 Signaling Pathway / cytokine-mediated signaling pathway / protein homooligomerization / positive regulation of interleukin-6 production / positive regulation of type II interferon production / 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 / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of canonical NF-kappaB signal transduction / cytoskeleton / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / 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
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-KRE / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.11 Å
AuthorsPinkas, D.M. / Bufton, J.C. / Kupinska, K. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust106169/Z/14/Z United Kingdom
CitationJournal: To be published
Title: Design of 3,5-diaryl-2-aminopyridines as receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors
Authors: Suebsuwong, C. / Dai, B. / Pinkas, D.M. / Bufton, J.C. / Duddupudi, A.L. / Li, L. / Hrdinka, M. / Schlicher, L. / Gyrd-Hansen, M. / Hu, M. / Bullock, A.N. / Degterev, A. / Cuny, G.D.
History
DepositionJun 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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
C: Receptor-interacting serine/threonine-protein kinase 2
D: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,3588
Polymers145,5434
Non-polymers1,8144
Water81145
1
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)73,6794
Polymers72,7722
Non-polymers9072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3770 Å2
ΔGint-26 kcal/mol
Surface area25990 Å2
MethodPISA
2
C: Receptor-interacting serine/threonine-protein kinase 2
D: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,6794
Polymers72,7722
Non-polymers9072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-25 kcal/mol
Surface area25370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.343, 124.343, 228.676
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11B-510-

HOH

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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: 36385.852 Da / Num. of mol.: 4
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-KRE / ~{N}-[3-[2-azanyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]-5-methoxy-phenyl]methanesulfonamide


Mass: 453.557 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H27N5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 3.04 Å3/Da / Density % sol: 59.49 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 150 nL sitting drops containing 100 nL protein and 50 nL of a reservoir solution containing the BCS5 condition 20% PEG Smear High, 0.1M citrate pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 3.11→69.7 Å / Num. obs: 32991 / % possible obs: 99.54 % / Redundancy: 12.7 % / Net I/σ(I): 4.82
Reflection shellResolution: 3.11→3.22 Å / Num. unique obs: 3199

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6FU5

6fu5


Resolution: 3.11→69.699 Å / SU ML: 0.57 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 33.61
RfactorNum. reflection% reflection
Rfree0.2996 1608 4.89 %
Rwork0.2536 --
obs0.2559 32868 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.11→69.699 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9249 0 128 45 9422
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049630
X-RAY DIFFRACTIONf_angle_d0.68713127
X-RAY DIFFRACTIONf_dihedral_angle_d17.9515775
X-RAY DIFFRACTIONf_chiral_restr0.0471467
X-RAY DIFFRACTIONf_plane_restr0.0041657
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1096-3.20990.43031360.38572702X-RAY DIFFRACTION97
3.2099-3.32470.41711560.37492760X-RAY DIFFRACTION99
3.3247-3.45780.42051240.35032818X-RAY DIFFRACTION99
3.4578-3.61510.38751580.30482795X-RAY DIFFRACTION100
3.6151-3.80570.34461370.28712805X-RAY DIFFRACTION100
3.8057-4.04410.32531540.26492821X-RAY DIFFRACTION100
4.0441-4.35640.27981440.21112830X-RAY DIFFRACTION100
4.3564-4.79470.23341410.18172876X-RAY DIFFRACTION100
4.7947-5.48820.22651590.19982846X-RAY DIFFRACTION100
5.4882-6.91360.28361390.23892938X-RAY DIFFRACTION100
6.9136-69.71640.2441600.22913069X-RAY DIFFRACTION100

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