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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 | ||||||
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Title | Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to RBM39 and Indisulam | ||||||
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![]() | ONCOPROTEIN / DDB1 | ||||||
Function / homology | ![]() 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 / UV-damage excision repair / regulation of mRNA splicing, via spliceosome / 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 / UV-damage excision repair / regulation of mRNA splicing, via spliceosome / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / WD40-repeat domain binding / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / immune system process / negative regulation of reproductive process / negative regulation of developmental process / small molecule binding / cullin family protein binding / centriolar satellite / viral release from host cell / 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 / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / mRNA processing / protein polyubiquitination / positive regulation of protein catabolic process / microtubule cytoskeleton / cellular response to UV / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / rhythmic process / Neddylation / protein-macromolecule adaptor activity / site of double-strand break / 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 / nucleolus / negative regulation of apoptotic process / apoptotic process / protein-containing complex / DNA binding / RNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / metal ion binding / cytoplasm Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.54 Å | ||||||
![]() | Srinivas, H. | ||||||
![]() | ![]() 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 |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 247.6 KB | Display | ![]() |
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PDB format | ![]() | 193.8 KB | Display | ![]() |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 10213MC ![]() 6ud7C ![]() 6ue5C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 66563.297 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 127097.469 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#3: Protein | Mass: 9085.409 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#4: Protein | Mass: 11724.102 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#5: Chemical | ChemComp-EF6 / |
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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Molecular weight | Value: 0.21 MDa / Experimental value: YES | ||||||||||||||||||||||||
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Source (recombinant) |
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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 |
Image recording | Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
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Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 380000 / Symmetry type: POINT |