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- PDB-6sj7: Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound... -

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Basic information

Entry
Database: PDB / ID: 6sj7
TitleStructure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to RBM39 and Indisulam
Components
  • DDB1- and CUL4-associated factor 15
  • DET1- and DDB1-associated protein 1
  • DNA damage-binding protein 1
  • RNA binding protein 39
KeywordsONCOPROTEIN / DDB1
Function / homology
Function and homology information


RS domain binding / regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / U1 snRNP binding / Cul4-RING E3 ubiquitin ligase complex / regulation of mRNA splicing, via spliceosome / UV-damage excision repair / biological process involved in interaction with symbiont ...RS domain binding / regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / U1 snRNP binding / Cul4-RING E3 ubiquitin ligase complex / regulation of mRNA splicing, via spliceosome / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / immune system process / negative regulation of reproductive process / negative regulation of developmental process / small molecule binding / viral release from host cell / cullin family protein binding / centriolar satellite / ectopic germ cell programmed cell death / proteasomal protein catabolic process / positive regulation of viral genome replication / RNA processing / positive regulation of gluconeogenesis / mRNA Splicing - Major Pathway / RNA splicing / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Wnt signaling pathway / Formation of Incision Complex in GG-NER / mRNA processing / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / protein polyubiquitination / positive regulation of protein catabolic process / cellular response to UV / microtubule cytoskeleton / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / site of double-strand break / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / nuclear speck / DNA repair / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / apoptotic process / protein-containing complex / DNA binding / RNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / metal ion binding / cytoplasm
Similarity search - Function
DDB1- and CUL4-associated factor 15, WD40 repeat-containing domain / DDB1- and CUL4-associated factor 15 / : / DDB1-and CUL4-substrate receptor 15, WD repeat / Splicing factor, RBM39-like / Splicing factor RBM39, linker / linker between RRM2 and RRM3 domains in RBM39 protein / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase ...DDB1- and CUL4-associated factor 15, WD40 repeat-containing domain / DDB1- and CUL4-associated factor 15 / : / DDB1-and CUL4-substrate receptor 15, WD repeat / Splicing factor, RBM39-like / Splicing factor RBM39, linker / linker between RRM2 and RRM3 domains in RBM39 protein / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / RNA recognition motif domain, eukaryote / RNA recognition motif / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / RRM (RNA recognition motif) domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily / Alpha-Beta Plaits / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EF6 / RNA-binding protein 39 / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 15 / Uncharacterized protein DKFZp781I1140 / DET1- and DDB1-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsSrinivas, H.
CitationJournal: Nat Chem Biol / Year: 2020
Title: Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.
Authors: Dirksen E Bussiere / Lili Xie / Honnappa Srinivas / Wei Shu / Ashley Burke / Celine Be / Junping Zhao / Adarsh Godbole / Dan King / Rajeshri G Karki / Viktor Hornak / Fangmin Xu / Jennifer ...Authors: Dirksen E Bussiere / Lili Xie / Honnappa Srinivas / Wei Shu / Ashley Burke / Celine Be / Junping Zhao / Adarsh Godbole / Dan King / Rajeshri G Karki / Viktor Hornak / Fangmin Xu / Jennifer Cobb / Nathalie Carte / Andreas O Frank / Alexandra Frommlet / Patrick Graff / Mark Knapp / Aleem Fazal / Barun Okram / Songchun Jiang / Pierre-Yves Michellys / Rohan Beckwith / Hans Voshol / Christian Wiesmann / Jonathan M Solomon / Joshiawa Paulk /
Abstract: The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase ...The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets.
History
DepositionAug 12, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: DDB1- and CUL4-associated factor 15
B: DNA damage-binding protein 1
C: RNA binding protein 39
D: DET1- and DDB1-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)214,8565
Polymers214,4704
Non-polymers3861
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13340 Å2
ΔGint-56 kcal/mol
Surface area52670 Å2
MethodPISA

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Components

#1: Protein DDB1- and CUL4-associated factor 15


Mass: 66563.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DCAF15, C19orf72 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q66K64
#2: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 127097.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#3: Protein RNA binding protein 39


Mass: 9085.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DKFZp781I1140 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q7Z3L0, UniProt: Q14498*PLUS
#4: Protein DET1- and DDB1-associated protein 1 / Placenta cross-immune reaction antigen 1 / PCIA-1


Mass: 11724.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDA1, C19orf58, PCIA1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BW61
#5: Chemical ChemComp-EF6 / N~1~-(3-chloro-1H-indol-7-yl)benzene-1,4-disulfonamide / Indisulam


Mass: 385.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12ClN3O4S2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antitumor, inhibitor, medication*YM
Has ligand of interestY
Has protein modificationY

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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
1DDB1 complexCOMPLEX#1-#40MULTIPLE SOURCES
2DDB1-DDA1-DCAF15-RBM39 complexCOMPLEX#1-#41RECOMBINANT
3RBM39COMPLEX#31RECOMBINANT
Molecular weightValue: 0.21 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
22Spodoptera frugiperda (fall armyworm)7108Sf21
33Escherichia coli BL21(DE3) (bacteria)469008
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 380000 / Symmetry type: POINT

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