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Open data
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Basic information
Entry | Database: PDB / ID: 8aza | ||||||
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Title | Structure of RIP2K dimer bound to the XIAP BIR2 domain | ||||||
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![]() | IMMUNE SYSTEM / kinase / BIR2 / complex / dimer | ||||||
Function / homology | ![]() response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of cytokine-mediated signaling pathway / positive regulation of protein linear polyubiquitination / immature T cell proliferation in thymus / regulation of BMP signaling pathway ...response to interleukin-18 / positive regulation of T-helper 1 cell differentiation / toll-like receptor 2 signaling pathway / endopeptidase regulator activity / regulation of apoptosis involved in tissue homeostasis / inhibition of cysteine-type endopeptidase activity / positive regulation of cytokine-mediated signaling pathway / positive regulation of protein linear polyubiquitination / immature T cell proliferation in thymus / regulation of BMP signaling pathway / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / copper ion homeostasis / 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 / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / 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 / SMAC, XIAP-regulated apoptotic response / Activation of caspases through apoptosome-mediated cleavage / Regulation of the apoptosome activity / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / positive regulation of macrophage cytokine production / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / toll-like receptor 4 signaling pathway / cysteine-type endopeptidase inhibitor activity / regulation of innate immune response / response to exogenous dsRNA / cellular response to lipoteichoic acid / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / protein K63-linked ubiquitination / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon production / canonical NF-kappaB signal transduction / positive regulation of interferon-alpha production / signaling adaptor activity / protein serine/threonine kinase binding / positive regulation of chemokine production / stress-activated MAPK cascade / JNK cascade / lipopolysaccharide-mediated signaling pathway / p75NTR recruits signalling complexes / positive regulation of interleukin-12 production / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / positive regulation of interferon-beta production / Regulation of PTEN localization / response to interleukin-1 / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of peptidyl-threonine phosphorylation / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of interleukin-1 beta production / positive regulation of protein ubiquitination / activated TAK1 mediates p38 MAPK activation / Deactivation of the beta-catenin transactivating complex / Regulation of TNFR1 signaling / 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 / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein homooligomerization / Regulation of necroptotic cell death / Wnt signaling pathway / cytokine-mediated signaling pathway / Regulation of PTEN stability and activity / Interleukin-1 signaling / ubiquitin-protein transferase activity / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / positive regulation of peptidyl-tyrosine phosphorylation / ubiquitin protein ligase activity / positive regulation of type II interferon production / Ovarian tumor domain proteases / positive regulation of canonical Wnt signaling pathway / 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 / regulation of cell population proliferation / regulation of inflammatory response / regulation of apoptotic process / neuron apoptotic process Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.15 Å | ||||||
![]() | Pellegrini, E. / Cusack, S. | ||||||
Funding support | 1items
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![]() | ![]() Title: Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface. Authors: Mathilde Lethier / Karine Huard / Michael Hons / Adrien Favier / Bernhard Brutscher / Elisabetta Boeri Erba / Derek W Abbott / Stephen Cusack / Erika Pellegrini / ![]() ![]() Abstract: RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the ...RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the phosphorylation activity of RIPK2 is dispensable for signalling and that inhibitors of both RIPK2 activity and RIPK2 ubiquitination prevent the essential interaction between RIPK2 and the BIR2 domain of XIAP, the key RIPK2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined native mass spectrometry, NMR, and cryo-electron microscopy to determine the structure of the RIPK2 kinase BIR2 domain complex and validated the interface with in cellulo assays. The structure shows that BIR2 binds across the RIPK2 kinase antiparallel dimer and provides an explanation for both inhibitory mechanisms. It also highlights why phosphorylation of the kinase activation loop is dispensable for signalling while revealing the structural role of RIPK2-K209 residue in the RIPK2-XIAP BIR2 interaction. Our results clarify the features of the RIPK2 conformation essential for its role as a scaffold protein for ubiquitination. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 135.6 KB | Display | ![]() |
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PDB format | ![]() | 103.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1 MB | Display | |
Data in XML | ![]() | 37.5 KB | Display | |
Data in CIF | ![]() | 53.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 15757MC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
Other databases |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 10229.517 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P98170, RING-type E3 ubiquitin transferase | ||||
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#2: Protein | Mass: 36412.879 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: O43353, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase #3: Chemical | ChemComp-ZN / | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 46.7 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173600 / Symmetry type: POINT | ||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||
Refine LS restraints |
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