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- PDB-8aza: Structure of RIP2K dimer bound to the XIAP BIR2 domain -

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Basic information

Entry
Database: PDB / ID: 8aza
TitleStructure of RIP2K dimer bound to the XIAP BIR2 domain
Components
  • E3 ubiquitin-protein ligase XIAP
  • Receptor-interacting serine/threonine-protein kinase 2
KeywordsIMMUNE SYSTEM / kinase / BIR2 / complex / dimer
Function / homology
Function and homology information


response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / endopeptidase regulator activity / inhibition of cysteine-type endopeptidase activity / regulation of apoptosis involved in tissue homeostasis / positive regulation of cytokine-mediated signaling pathway / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / immature T cell proliferation in thymus ...response to interleukin-18 / toll-like receptor 2 signaling pathway / positive regulation of T-helper 1 cell differentiation / endopeptidase regulator activity / inhibition of cysteine-type endopeptidase activity / regulation of apoptosis involved in tissue homeostasis / positive regulation of cytokine-mediated signaling pathway / positive regulation of protein linear polyubiquitination / regulation of BMP signaling pathway / immature T cell proliferation in thymus / positive regulation of T-helper 1 type immune response / positive regulation of xenophagy / copper ion homeostasis / xenophagy / LIM domain binding / positive regulation of protein K63-linked ubiquitination / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / nucleotide-binding oligomerization domain containing 1 signaling pathway / cellular response to muramyl dipeptide / caspase binding / CD4-positive, alpha-beta T cell proliferation / positive regulation of stress-activated MAPK cascade / CARD domain binding / positive regulation of immature T cell proliferation in thymus / JUN kinase kinase kinase activity / cellular response to peptidoglycan / response to interleukin-12 / positive regulation of CD4-positive, alpha-beta T cell proliferation / nucleotide-binding oligomerization domain containing 2 signaling pathway / activation of cysteine-type endopeptidase activity / 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 / TNFR1-induced proapoptotic signaling / positive regulation of macrophage cytokine production / RIPK1-mediated regulated necrosis / toll-like receptor 4 signaling pathway / cysteine-type endopeptidase inhibitor activity / regulation of innate immune response / response to exogenous dsRNA / positive regulation of interferon-alpha production / cellular response to lipoteichoic acid / protein K63-linked ubiquitination / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / negative regulation of tumor necrosis factor-mediated signaling pathway / positive regulation of type I interferon production / canonical NF-kappaB signal transduction / protein serine/threonine kinase binding / signaling adaptor activity / stress-activated MAPK cascade / positive regulation of chemokine production / JNK cascade / lipopolysaccharide-mediated signaling pathway / positive regulation of interleukin-12 production / positive regulation of interferon-beta production / positive regulation of interleukin-2 production / ERK1 and ERK2 cascade / p75NTR recruits signalling complexes / response to interleukin-1 / Regulation of PTEN localization / : / 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 / TNFR1-induced NF-kappa-B signaling pathway / activated TAK1 mediates p38 MAPK activation / Deactivation of the beta-catenin transactivating complex / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / Regulation of TNFR1 signaling / non-membrane spanning protein tyrosine kinase activity / TAK1-dependent IKK and NF-kappa-B activation / RING-type E3 ubiquitin transferase / NOD1/2 Signaling Pathway / protein homooligomerization / Regulation of necroptotic cell death / Wnt signaling pathway / cytokine-mediated signaling pathway / Regulation of PTEN stability and activity / positive regulation of interleukin-6 production / Interleukin-1 signaling / positive regulation of type II interferon production / ubiquitin-protein transferase activity / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / ubiquitin protein ligase activity / positive regulation of canonical Wnt signaling pathway / 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 / regulation of cell population proliferation / regulation of inflammatory response / regulation of apoptotic process / neuron apoptotic process
Similarity search - Function
Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / : / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. ...Receptor-interacting serine/threonine-protein kinase 2 / RIP2, CARD domain / XIAP/BIRC8, UBA domain / : / BIRC2/3-like, UBA domain / : / BIR repeat. / BIR repeat / Inhibitor of Apoptosis domain / BIR repeat profile. / Baculoviral inhibition of apoptosis protein repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / : / Zinc finger, C3HC4 type (RING finger) / Death-like domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Similarity search - Domain/homology
Receptor-interacting serine/threonine-protein kinase 2 / E3 ubiquitin-protein ligase XIAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsPellegrini, E. / Cusack, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Life Sci Alliance / Year: 2023
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
DepositionSep 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 26, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: E3 ubiquitin-protein ligase XIAP
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)83,1214
Polymers83,0553
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein E3 ubiquitin-protein ligase XIAP / Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of ...Baculoviral IAP repeat-containing protein 4 / IAP-like protein / ILP / hILP / Inhibitor of apoptosis protein 3 / IAP-3 / hIAP-3 / hIAP3 / RING-type E3 ubiquitin transferase XIAP / X-linked inhibitor of apoptosis protein / X-linked IAP


Mass: 10229.517 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XIAP, API3, BIRC4, IAP3 / Production host: Escherichia coli (E. coli)
References: UniProt: P98170, RING-type E3 ubiquitin transferase
#2: 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: 36412.879 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
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1dimeric RIP2K bound to XIAP BIR2 domainCOMPLEX#1-#20MULTIPLE SOURCES
2RIP2K dimerCOMPLEX#21RECOMBINANT
3BIR2 domain of E3 ligase XIAPCOMPLEX#11RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 46.7 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10cryoSPARC3.3.2initial Euler assignment
11cryoSPARC3.3.2final Euler assignment
12cryoSPARC3.3.2classification
13cryoSPARC3.3.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173600 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045166
ELECTRON MICROSCOPYf_angle_d0.7737011
ELECTRON MICROSCOPYf_dihedral_angle_d4.184671
ELECTRON MICROSCOPYf_chiral_restr0.046770
ELECTRON MICROSCOPYf_plane_restr0.007889

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