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- PDB-8dso: Structure of cIAP1, BTK and BCCov -

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Basic information

Entry
Database: PDB / ID: 8dso
TitleStructure of cIAP1, BTK and BCCov
Components
  • Baculoviral IAP repeat-containing protein 2
  • Tyrosine-protein kinase BTK
KeywordsONCOPROTEIN / E3 Ligase / PROTAC / Ternary Complex / BTK
Function / homology
Function and homology information


negative regulation of ripoptosome assembly involved in necroptotic process / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of B cell cytokine production / regulation of necroptotic process / regulation of B cell apoptotic process / positive regulation of protein K63-linked ubiquitination ...negative regulation of ripoptosome assembly involved in necroptotic process / FBXO family protein binding / regulation of RIG-I signaling pathway / positive regulation of protein K48-linked ubiquitination / regulation of non-canonical NF-kappaB signal transduction / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of B cell cytokine production / regulation of necroptotic process / regulation of B cell apoptotic process / positive regulation of protein K63-linked ubiquitination / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / CD40 receptor complex / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / negative regulation of necroptotic process / XY body / positive regulation of type I hypersensitivity / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / non-canonical NF-kappaB signal transduction / positive regulation of protein monoubiquitination / TNFR1-induced proapoptotic signaling / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / RIPK1-mediated regulated necrosis / regulation of reactive oxygen species metabolic process / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / phospholipase activator activity / regulation of toll-like receptor signaling pathway / regulation of innate immune response / negative regulation of interleukin-10 production / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / mesoderm development / necroptotic process / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / regulation of cell differentiation / response to cAMP / canonical NF-kappaB signal transduction / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / TICAM1, RIP1-mediated IKK complex recruitment / placenta development / IKK complex recruitment mediated by RIP1 / ubiquitin binding / positive regulation of protein ubiquitination / tumor necrosis factor-mediated signaling pathway / TNFR1-induced NF-kappa-B signaling pathway / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / TNFR2 non-canonical NF-kB pathway / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / Regulation of TNFR1 signaling / calcium-mediated signaling / NOD1/2 Signaling Pathway / positive regulation of NF-kappaB transcription factor activity / RING-type E3 ubiquitin transferase / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / positive regulation of interleukin-6 production / cytoplasmic side of plasma membrane / protein polyubiquitination / G beta:gamma signalling through BTK / ubiquitin-protein transferase activity / positive regulation of tumor necrosis factor production / ubiquitin protein ligase activity / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / regulation of cell population proliferation / protein-folding chaperone binding / transferase activity / ER-Phagosome pathway / regulation of inflammatory response / cytoplasmic vesicle / protein tyrosine kinase activity
Similarity search - Function
BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / : / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. ...BIRC2/BIRC3, UBA domain / : / BIRC2/3-like, UBA domain / : / Caspase recruitment domain / BIR repeat. / Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / 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) / PH domain / : / Death-like domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Ring finger / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Zinc finger RING-type profile. / SH2 domain / Zinc finger, RING-type / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-TOO / Tyrosine-protein kinase BTK / Baculoviral IAP repeat-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.334 Å
AuthorsSchiemer, J.S. / Calabrese, M.F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: A covalent BTK ternary complex compatible with targeted protein degradation.
Authors: Schiemer, J. / Maxwell, A. / Horst, R. / Liu, S. / Uccello, D.P. / Borzilleri, K. / Rajamohan, N. / Brown, M.F. / Calabrese, M.F.
History
DepositionJul 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Tyrosine-protein kinase BTK
D: Baculoviral IAP repeat-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6054
Polymers43,4322
Non-polymers1,1742
Water1,29772
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.36, 104.36, 110.29
Angle α, β, γ (deg.)90, 90, 120
Int Tables number150
Space group name H-MP321

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Components

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 32112.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Protein Baculoviral IAP repeat-containing protein 2 / Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / ...Cellular inhibitor of apoptosis 1 / C-IAP1 / IAP homolog B / Inhibitor of apoptosis protein 2 / hIAP2 / RING finger protein 48 / RING-type E3 ubiquitin transferase BIRC2 / TNFR2-TRAF-signaling complex protein 2


Mass: 11318.731 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BIRC2, API1, MIHB, RNF48 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13490, RING-type E3 ubiquitin transferase
#3: Chemical ChemComp-TOO / (4S)-4-[2-(2-{4-[(2E)-4-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}-4-oxobut-2-en-1-yl]piperazin-1-yl}ethoxy)acetamido]-1-{(2S)-2-cyclohexyl-2-[(N-methyl-L-alanyl)amino]acetyl}-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-L-prolinamide bound form


Mass: 1108.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C61H81N13O7 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.99 Å3/Da / Density % sol: 70.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 0.1 M BTP pH 9, 4M potassium formate, and 2% PEG MME 2K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.334→110.29 Å / Num. obs: 17804 / % possible obs: 88.9 % / Redundancy: 9.9 % / Rpim(I) all: 0.113 / Net I/σ(I): 4.7
Reflection shellResolution: 2.337→2.734 Å / Num. unique obs: 890 / Rpim(I) all: 0.551

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5p9j

5p9j


Resolution: 2.334→110.29 Å / Cor.coef. Fo:Fc: 0.903 / Cor.coef. Fo:Fc free: 0.88 / SU R Cruickshank DPI: 0.456 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.446 / SU Rfree Blow DPI: 0.319 / SU Rfree Cruickshank DPI: 0.322
RfactorNum. reflection% reflectionSelection details
Rfree0.2918 854 -RANDOM
Rwork0.2423 ---
obs0.2446 17804 59.3 %-
Displacement parametersBiso mean: 70.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.3827 Å20 Å20 Å2
2---0.3827 Å20 Å2
3---0.7653 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: LAST / Resolution: 2.334→110.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2683 0 82 72 2837
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082925HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.934046HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d959SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes525HARMONIC5
X-RAY DIFFRACTIONt_it2844HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion353SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2242SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.58
X-RAY DIFFRACTIONt_other_torsion19.27
LS refinement shellResolution: 2.334→2.53 Å
RfactorNum. reflection% reflection
Rfree0.5295 12 -
Rwork0.3443 --
obs--6.7 %

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