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- PDB-6q0r: Structure of DDB1-DDA1-DCAF15 complex bound to E7820 and RBM39 -

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Basic information

Entry
Database: PDB / ID: 6q0r
TitleStructure of DDB1-DDA1-DCAF15 complex bound to E7820 and RBM39
Components
  • (DDB1- and CUL4-associated factor ...) x 2
  • DET1- and DDB1-associated protein 1
  • DNA damage-binding protein 1
  • RNA-binding protein 39
KeywordsLIGASE / 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 / U1 snRNP binding / regulation of mRNA splicing, via spliceosome / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition ...RS domain binding / regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / U1 snRNP binding / regulation of mRNA splicing, via spliceosome / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / Cul4-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / small molecule binding / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / viral release from host cell / immune system process / ectopic germ cell programmed cell death / positive regulation of viral genome replication / RNA processing / proteasomal protein catabolic process / positive regulation of gluconeogenesis / mRNA Splicing - Major Pathway / RNA splicing / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / centriolar satellite / Formation of Incision Complex in GG-NER / Wnt signaling pathway / mRNA processing / protein polyubiquitination / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / microtubule cytoskeleton / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / nuclear speck / protein ubiquitination / DNA repair / apoptotic process / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / protein-containing complex / extracellular space / DNA binding / RNA binding / extracellular exosome / nucleoplasm / metal ion binding / nucleus / 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 / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / RRM (RNA recognition motif) domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-O6M / OXAMIC ACID / 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 speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsFaust, 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
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214608 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)1F32CA232772-01 United States
CitationJournal: 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
DepositionAug 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2019Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 1, 2020Group: 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 1.4Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)185,0268
Polymers184,5355
Non-polymers4913
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy, cryo-electron microscopy structure to 4.4 A confirms the overall assembly
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20620 Å2
ΔGint-103 kcal/mol
Surface area52900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.108, 93.6, 258.439
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 3 types, 3 molecules ADE

#1: 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: 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
#4: Protein RNA-binding protein 39 / CAPER alpha / Hepatocellular carcinoma protein 1 / RNA-binding motif protein 39 / RNA-binding ...CAPER alpha / Hepatocellular carcinoma protein 1 / RNA-binding motif protein 39 / RNA-binding region-containing protein 2 / Splicing factor HCC1


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 DET1- and DDB1-associated protein 1 / Placenta cross-immune reaction antigen 1 / PCIA-1


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

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DDB1- and CUL4-associated factor ... , 2 types, 2 molecules BC

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


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


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

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Non-polymers , 4 types, 19 molecules

#6: Chemical ChemComp-OXM / OXAMIC ACID


Mass: 89.050 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3NO3
#7: Chemical ChemComp-O6M / 3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide


Mass: 336.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12N4O2S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Zn
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.65 Å3/Da / Density % sol: 53.62 %
Crystal growTemperature: 300 K / Method: vapor diffusion / Details: 20% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 8, 2019
RadiationMonochromator: Cryo cooled double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 44491 / % possible obs: 99.5 % / Redundancy: 6.7 % / Biso Wilson estimate: 102.82 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.03 / Net I/σ(I): 14.7
Reflection shellResolution: 2.9→3 Å / Rmerge(I) obs: 0.8 / Num. unique obs: 4381 / CC1/2: 0.69

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDS20190315data reduction
Aimless0.7.4data scaling
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5fqd chain A

5fqd


Resolution: 2.9→46.05 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.9 / SU R Cruickshank DPI: 1.016 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.936 / SU Rfree Blow DPI: 0.341 / SU Rfree Cruickshank DPI: 0.349
RfactorNum. reflection% reflectionSelection details
Rfree0.251 2210 -RANDOM
Rwork0.205 ---
obs0.207 44491 99.8 %-
Displacement parametersBiso mean: 133.23 Å2
Baniso -1Baniso -2Baniso -3
1-30.9592 Å20 Å20 Å2
2---21.5941 Å20 Å2
3----9.3651 Å2
Refine analyzeLuzzati coordinate error obs: 0.44 Å
Refinement stepCycle: LAST / Resolution: 2.9→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10202 0 31 16 10249
LS refinement shellResolution: 2.9→2.92 Å
RfactorNum. reflection% reflection
Rfree0.2719 49 -
Rwork0.2419 --
obs0.2436 890 97.31 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.5118-0.1533-0.06041.3730.83681.6777-0.22390.1168-0.02610.11680.05160.1133-0.02610.11330.1723-0.33110.1074-0.06360.3215-0.304-0.0002-43.76925.8131-21.8164
23.56521.29631.5983.2691.6412.4224-0.02940.08940.52040.08940.22360.72140.52040.7214-0.1942-0.17440.1848-0.0316-0.1991-0.09390.017-23.191-14.1691-48.4023
33.22141.47260.60912.97341.10672.2436-0.19770.06110.56370.0611-0.07320.1240.56370.1240.27090.09850.13260.0676-0.2979-0.06170.1028-40.6061-25.6584-55.3884
44.67060.91312.62910.5182-0.40427.7589-0.3862-0.7032-0.1366-0.70320.37190.5917-0.13660.59170.0143-0.0461-0.0239-0.0238-0.2908-0.01230.1351-36.5398-5.837-68.3181
56.19460.292-0.61690.69050.90043.6143-0.19760.00120.52650.0012-0.2849-0.59780.5265-0.59780.4825-0.46860.01820.09850.1143-0.1104-0.0659-62.6265-10.0052-27.5934
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }

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