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Yorodumi- PDB-6q0v: Structure of DDB1-DDA1-DCAF15 complex bound to tasisulam and RBM39 -
+Open data
-Basic information
Entry | Database: PDB / ID: 6q0v | |||||||||
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Title | Structure of DDB1-DDA1-DCAF15 complex bound to tasisulam and RBM39 | |||||||||
Components |
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Keywords | LIGASE / Ubiquitin / homeostasis / targeted protein degradation | |||||||||
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 / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / immune system process / small molecule binding / negative regulation of reproductive process / negative regulation of developmental process / viral release from host cell / cullin family protein binding / ectopic germ cell programmed cell death / centriolar satellite / 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 / mRNA processing / 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 / site of double-strand break / Neddylation / 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å | |||||||||
Authors | 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 | United States, 2items
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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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6q0v.cif.gz | 558.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6q0v.ent.gz | 455.1 KB | Display | PDB format |
PDBx/mmJSON format | 6q0v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6q0v_validation.pdf.gz | 857.1 KB | Display | wwPDB validaton report |
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Full document | 6q0v_full_validation.pdf.gz | 875.4 KB | Display | |
Data in XML | 6q0v_validation.xml.gz | 45 KB | Display | |
Data in CIF | 6q0v_validation.cif.gz | 62.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/q0/6q0v ftp://data.pdbj.org/pub/pdb/validation_reports/q0/6q0v | HTTPS FTP |
-Related structure data
Related structure data | 6q0rSC 6q0wC S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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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.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531 |
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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.) Homo sapiens (human) / Gene: RBM39, HCC1, RNPC2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q14498 |
#5: Protein | Mass: 14542.154 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: DDA1, C19orf58, PCIA1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BW61 |
-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.) Homo sapiens (human) / Gene: DCAF15, C19orf72 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q66K64 |
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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.) Homo sapiens (human) / Gene: DCAF15, C19orf72 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q66K64 |
-Non-polymers , 3 types, 19 molecules
#6: Chemical | ChemComp-P7M / |
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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: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.73 Å3/Da / Density % sol: 54.93 % |
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Crystal grow | Temperature: 300 K / Method: vapor diffusion / Details: 20% PEG 4000 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 1.6531 Å |
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: 1.6531 Å / Relative weight: 1 |
Reflection | Resolution: 2.9→47.31 Å / Num. obs: 45408 / % possible obs: 99.7 % / Redundancy: 39.1 % / CC1/2: 0.99 / Rmerge(I) obs: 0.217 / Net I/σ(I): 15.3 |
Reflection shell | Resolution: 2.9→3 Å / Rmerge(I) obs: 5.368 / Num. unique obs: 4298 / CC1/2: 0.77 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 6Q0R Resolution: 2.9→46.55 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.889 / SU R Cruickshank DPI: 1.053 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.93 / SU Rfree Blow DPI: 0.328 / SU Rfree Cruickshank DPI: 0.337
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Displacement parameters | Biso mean: 120.26 Å2
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Refine analyze | Luzzati coordinate error obs: 0.42 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.9→46.55 Å
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LS refinement shell | Resolution: 2.9→2.93 Å
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Refinement TLS params. | Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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