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- PDB-6q0w: Structure of DDB1-DDA1-DCAF15 complex bound to Indisulam and RBM39 -
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Open data
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Basic information
Entry | Database: PDB / ID: 6q0w | |||||||||
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Title | Structure of DDB1-DDA1-DCAF15 complex bound to Indisulam and RBM39 | |||||||||
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![]() | LIGASE / Ubiquitin / homeostasis / targeted protein degradation | |||||||||
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 / 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 / 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 / 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 / cellular response to UV / microtubule cytoskeleton / 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 | |||||||||
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Method | ![]() ![]() ![]() | |||||||||
![]() | Faust, T. / Yoon, H. / Nowak, R.P. / Donovan, K.A. / Li, Z. / Cai, Q. / Eleuteri, N.A. / Zhang, T. / Gray, N.S. / Fischer, E.S. | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 559.8 KB | Display | ![]() |
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PDB format | ![]() | 457.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 343.7 KB | Display | ![]() |
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Full document | ![]() | 343.7 KB | Display | |
Data in XML | ![]() | 1.2 KB | Display | |
Data in CIF | ![]() | 13.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6q0rSC ![]() 6q0vC S: Starting model for refinement 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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Unit cell |
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Components
-Protein , 3 types, 3 molecules ADE
#1: Protein | Mass: 96425.586 Da / Num. of mol.: 1 / Fragment: internal deletion of the BPB domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#4: Protein | Mass: 12062.565 Da / Num. of mol.: 1 / Fragment: RRM2 domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#5: Protein | Mass: 14542.154 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-DDB1- and CUL4-associated factor ... , 2 types, 2 molecules BC
#2: Protein | Mass: 31611.043 Da / Num. of mol.: 1 / Fragment: N-terminal domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#3: Protein | Mass: 29893.537 Da / Num. of mol.: 1 / Fragment: C-terminal domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Non-polymers , 3 types, 7 molecules ![](data/chem/img/EF6.gif)
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#6: Chemical | ChemComp-EF6 / |
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#7: Chemical | ChemComp-ZN / |
#8: Water | ChemComp-HOH / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.72 Å3/Da / Density % sol: 54.74 % |
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Crystal grow | Temperature: 300 K / Method: vapor diffusion / Details: 20% PEG 4000 |
-Data collection
Diffraction | Mean temperature: 100 K / Ambient temp details: N2 / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 24, 2019 |
Radiation | Monochromator: Cryo cooled double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9792 Å / Relative weight: 1 |
Reflection | Resolution: 2.9→46.99 Å / Num. obs: 45547 / % possible obs: 99 % / Redundancy: 6.7 % / CC1/2: 0.99 / Rmerge(I) obs: 0.16 / Net I/σ(I): 7 |
Reflection shell | Resolution: 2.9→3 Å / Rmerge(I) obs: 2.6 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 4294 / CC1/2: 0.584 / % possible all: 97.3 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 6Q0R Resolution: 2.9→46.99 Å / Cor.coef. Fo:Fc: 0.886 / Cor.coef. Fo:Fc free: 0.867 / SU R Cruickshank DPI: 1.243 / Cross valid method: THROUGHOUT / SU R Blow DPI: 1.132 / SU Rfree Blow DPI: 0.36 / SU Rfree Cruickshank DPI: 0.368
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Displacement parameters | Biso mean: 125.29 Å2
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Refine analyze | Luzzati coordinate error obs: 0.55 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.9→46.99 Å
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LS refinement shell | Resolution: 2.9→2.92 Å
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Refinement TLS params. | Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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