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- PDB-6fu5: Structure of the kinase domain of human RIPK2 in complex with the... -

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Basic information

Entry
Database: PDB / ID: 6fu5
TitleStructure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP18
ComponentsReceptor-interacting serine/threonine-protein kinase 2
KeywordsTRANSFERASE
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 / LIM domain binding / positive regulation of xenophagy / CD4-positive, alpha-beta T cell proliferation / xenophagy ...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 / LIM domain binding / positive regulation of xenophagy / CD4-positive, alpha-beta T cell proliferation / xenophagy / 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 / positive regulation of CD4-positive, alpha-beta T cell proliferation / cellular response to peptidoglycan / response to interleukin-12 / 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 / signaling adaptor activity / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / ERK1 and ERK2 cascade / p75NTR recruits signalling complexes / positive regulation of interleukin-2 production / positive regulation of interferon-beta production / positive regulation of interleukin-12 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 protein ubiquitination / positive regulation of interleukin-1 beta production / activated TAK1 mediates p38 MAPK activation / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / TAK1-dependent IKK and NF-kappa-B activation / NOD1/2 Signaling Pathway / non-membrane spanning protein tyrosine kinase activity / protein homooligomerization / positive regulation of interleukin-6 production / Interleukin-1 signaling / cytokine-mediated signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / Ovarian tumor domain proteases / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / Downstream TCR signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of NF-kappaB transcription factor activity / positive regulation of protein binding / 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 / 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-E7N / Receptor-interacting serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.26 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.
CitationJournal: EMBO J. / Year: 2018
Title: Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.
Authors: Hrdinka, M. / Schlicher, L. / Dai, B. / Pinkas, D.M. / Bufton, J.C. / Picaud, S. / Ward, J.A. / Rogers, C. / Suebsuwong, C. / Nikhar, S. / Cuny, G.D. / Huber, K.V. / Filippakopoulos, P. / ...Authors: Hrdinka, M. / Schlicher, L. / Dai, B. / Pinkas, D.M. / Bufton, J.C. / Picaud, S. / Ward, J.A. / Rogers, C. / Suebsuwong, C. / Nikhar, S. / Cuny, G.D. / Huber, K.V. / Filippakopoulos, P. / Bullock, A.N. / Degterev, A. / Gyrd-Hansen, M.
History
DepositionFeb 26, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 1, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 29, 2018Group: Data collection / Structure summary / Category: struct_keywords
Item: _struct_keywords.pdbx_keywords / _struct_keywords.text
Revision 1.3Sep 12, 2018Group: Data collection / Database references / Category: citation / Item: _citation.journal_volume
Revision 1.4Jan 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:
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)73,7354
Polymers72,7722
Non-polymers9632
Water1629
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3880 Å2
ΔGint-25 kcal/mol
Surface area25340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.790, 122.710, 71.450
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: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-E7N / ~{N}-[5-[2-azanyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]-2-methoxy-phenyl]propane-1-sulfonamide


Mass: 481.610 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H31N5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 2.28 Å3/Da / Density % sol: 46.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 150 nL sitting drops containing 50 nL protein and 100 nL of a reservoir solution containing 0.2 M potassium formate and 20% (w/v) PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3.26→39.66 Å / Num. obs: 10837 / % possible obs: 99.48 % / Redundancy: 6 % / Net I/σ(I): 7.12
Reflection shellResolution: 3.26→3.377 Å

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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: 4C8B

4c8b


Resolution: 3.26→39.66 Å / SU ML: 0.52 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.34
RfactorNum. reflection% reflection
Rfree0.271 539 4.98 %
Rwork0.2292 --
obs0.2313 10834 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.26→39.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4557 0 68 9 4634
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034748
X-RAY DIFFRACTIONf_angle_d0.5516467
X-RAY DIFFRACTIONf_dihedral_angle_d19.9042857
X-RAY DIFFRACTIONf_chiral_restr0.042721
X-RAY DIFFRACTIONf_plane_restr0.003818
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2601-3.58810.36421400.32442511X-RAY DIFFRACTION99
3.5881-4.1070.30851230.2492535X-RAY DIFFRACTION100
4.107-5.17330.2771380.2122570X-RAY DIFFRACTION99
5.1733-100.22941380.20872679X-RAY DIFFRACTION99

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