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- PDB-6es0: Crystal structure of the kinase domain of human RIPK2 in complex ... -

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Basic information

Entry
Database: PDB / ID: 6es0
TitleCrystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTRANSFERASE / Kinase Inhibitor
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-BW8 / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsPinkas, D.M. / Bufton, J.C. / Suebsuwong, C. / Ray, S.S. / Dai, B. / Newman, J.A. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. ...Pinkas, D.M. / Bufton, J.C. / Suebsuwong, C. / Ray, S.S. / Dai, B. / Newman, J.A. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Degterev, A. / Cuny, G.D. / Bullock, A.N.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.
Authors: Suebsuwong, C. / Pinkas, D.M. / Ray, S.S. / Bufton, J.C. / Dai, B. / Bullock, A.N. / Degterev, A. / Cuny, G.D.
History
DepositionOct 19, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 17, 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:
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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)73,7494
Polymers72,7722
Non-polymers9772
Water3,513195
1
A: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8742
Polymers36,3861
Non-polymers4881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Receptor-interacting serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8742
Polymers36,3861
Non-polymers4881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.980, 83.740, 139.100
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RIPK2, CARDIAK, RICK, RIP2, UNQ277/PRO314/PRO34092 / Production host: Escherichia coli (E. coli)
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-BW8 / 2-[2-fluoranyl-4-[[2-fluoranyl-4-[2-(methylcarbamoyl)pyridin-4-yl]oxy-phenyl]carbamoylamino]phenyl]sulfanylethanoic acid


Mass: 488.464 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18F2N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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: 2.48 Å3/Da / Density % sol: 50.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 25% PEG Smear Low -- 0.1M MES pH 6.5 -- 0.05M magnesium acetate -- 0.05M magnesium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 2.38→71.74 Å / Num. obs: 29591 / % possible obs: 99.41 % / Redundancy: 4.6 % / Net I/σ(I): 16.05

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
X-Areadata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4C8B

4c8b


Resolution: 2.38→71.74 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / Phase error: 25.8
RfactorNum. reflection% reflection
Rfree0.2576 1480 5 %
Rwork0.2135 --
obs0.2157 29588 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.38→71.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4638 0 68 195 4901
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024834
X-RAY DIFFRACTIONf_angle_d0.5816579
X-RAY DIFFRACTIONf_dihedral_angle_d16.2492883
X-RAY DIFFRACTIONf_chiral_restr0.043728
X-RAY DIFFRACTIONf_plane_restr0.004835
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.38-2.45690.3511330.29222509X-RAY DIFFRACTION100
2.4569-2.54470.31721320.27292523X-RAY DIFFRACTION100
2.5447-2.64660.32631320.27152498X-RAY DIFFRACTION100
2.6466-2.7670.33611320.26532537X-RAY DIFFRACTION99
2.767-2.91290.31481340.24442537X-RAY DIFFRACTION99
2.9129-3.09540.28771350.23592543X-RAY DIFFRACTION99
3.0954-3.33440.24881320.21342522X-RAY DIFFRACTION99
3.3344-3.66990.24131340.19022560X-RAY DIFFRACTION100
3.6699-4.20090.23741350.17722562X-RAY DIFFRACTION99
4.2009-5.29250.20311380.17162603X-RAY DIFFRACTION99
5.2925-71.77520.22761430.20852714X-RAY DIFFRACTION99

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