- EMDB-20553: Cryo-EM structure of DDB1dB-DCAF15-DDA1 bound to E7820 and RBM39 -
+
Open data
ID or keywords:
Loading...
-
Basic information
Entry
Database: EMDB / ID: EMD-20553
Title
Cryo-EM structure of DDB1dB-DCAF15-DDA1 bound to E7820 and RBM39
Map data
Final refinement map
Sample
Complex: Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39
Protein or peptide: DNA damage-binding protein 1
Protein or peptide: DDB1 and CUL4 associated factor 15
Protein or peptide: RNA binding motif protein 39
Protein or peptide: DET1 And DDB1 Associated 1
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 / 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 / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / 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 / cullin family protein binding / viral release from host cell / centriolar satellite / ectopic germ cell programmed cell death / small molecule binding / proteasomal protein catabolic process / positive regulation of viral genome replication / RNA processing / positive regulation of gluconeogenesis / RNA splicing / mRNA Splicing - Major Pathway / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / mRNA processing / 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 / protein polyubiquitination / positive regulation of protein catabolic process / microtubule cytoskeleton / cellular response to UV / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / Neddylation / site of double-strand break / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / chromosome, telomeric region / damaged DNA binding / protein ubiquitination / nuclear speck / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / nucleolus / negative regulation of 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 / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / Splicing factor, RBM39-like / Splicing factor RBM39, linker / linker between RRM2 and RRM3 domains in RBM39 protein ...DDB1- and CUL4-associated factor 15, WD40 repeat-containing domain / DDB1- and CUL4-associated factor 15 / : / DDB1-and CUL4-substrate receptor 15, WD repeat / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / Splicing factor, RBM39-like / Splicing factor RBM39, linker / linker between RRM2 and RRM3 domains in RBM39 protein / 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 / 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 / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily Similarity search - Domain/homology
RNA-binding protein 39 / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 15 / DET1- and DDB1-associated protein 1 Similarity search - Component
Biological species
Homo sapiens (human)
Method
single particle reconstruction / cryo EM / Resolution: 4.4 Å
National Institutes of Health/National Cancer Institute
R01CA214608
United States
Citation
Journal: Nat Chem Biol / Year: 2020 Title: Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Authors: Tyler B Faust / Hojong Yoon / Radosław P Nowak / Katherine A Donovan / Zhengnian Li / Quan Cai / Nicholas A Eleuteri / Tinghu Zhang / Nathanael S Gray / Eric S Fischer / Abstract: The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically ...The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.
History
Deposition
Aug 2, 2019
-
Header (metadata) release
Aug 14, 2019
-
Map release
Nov 20, 2019
-
Update
Nov 25, 2020
-
Current status
Nov 25, 2020
Processing site: RCSB / Status: Released
-
Structure visualization
Movie
Surface view with section colored by density value
Entire : Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39
Entire
Name: Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39
Components
Complex: Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39
Protein or peptide: DNA damage-binding protein 1
Protein or peptide: DDB1 and CUL4 associated factor 15
Protein or peptide: RNA binding motif protein 39
Protein or peptide: DET1 And DDB1 Associated 1
-
Supramolecule #1: Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39
Supramolecule
Name: Complex of DDB1-DCAF15-DDA1 bound to E7820 and the second RRM of RBM39 type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: Compound: E7820; Chemical Name: 3-Cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide
Source (natural)
Organism: Homo sapiens (human)
Recombinant expression
Organism: Trichoplusia ni (cabbage looper)
Molecular weight
Theoretical: 193 KDa
-
Macromolecule #1: DNA damage-binding protein 1
Macromolecule
Name: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Details: Gel filtration buffer was made fresh the day of the purification
Grid
Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
Vitrification
Cryogen name: ETHANE / Chamber humidity: 99 % / Chamber temperature: 286 K / Instrument: LEICA EM GP / Details: Blotted for 3 seconds before plunging..
Details
This sample was monodisperse
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Phase plate: VOLTA PHASE PLATE
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 2 / Number real images: 9393 / Average electron dose: 54.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi