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- PDB-6ud7: Crystal structure of full-length human DCAF15-DDB1(deltaBPB)-DDA1... -

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Basic information

Entry
Database: PDB / ID: 6ud7
TitleCrystal structure of full-length human DCAF15-DDB1(deltaBPB)-DDA1-RBM39 in complex with indisulam
Components
  • DDB1- and CUL4-associated factor 15
  • DET1- and DDB1-associated protein 1
  • DNA damage-binding protein 1,DNA damage-binding protein 1
  • RNA-binding motif protein 39
KeywordsLIGASE / E3 ligase / neosubstrate
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 / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / 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 / U1 snRNP binding / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / 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 / 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 / small molecule binding / centriolar satellite / viral release from host cell / ectopic germ cell programmed cell death / positive regulation of viral genome replication / RNA processing / positive regulation of gluconeogenesis / mRNA Splicing - Major Pathway / RNA splicing / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / regulation of circadian rhythm / 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 / protein polyubiquitination / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / 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 / extracellular space / 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 / 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 / RRM (RNA recognition motif) domain / 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 / Alpha-Beta Plaits / WD40/YVTN repeat-like-containing domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EF6 / RNA-binding protein 39 / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 15 / Uncharacterized protein DKFZp781I1140 / DET1- and DDB1-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsBussiere, D.E. / Shu, W. / Xie, L. / Knapp, M.
CitationJournal: Nat Chem Biol / Year: 2020
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
DepositionSep 18, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)181,2907
Polymers180,7204
Non-polymers5703
Water13,403744
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15100 Å2
ΔGint-63 kcal/mol
Surface area58680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.032, 93.778, 264.639
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 4 molecules ABCD

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


Mass: 66563.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DCAF15, C19orf72 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q66K64
#2: Protein DNA damage-binding protein 1,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: 93347.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#3: Protein RNA-binding motif protein 39


Mass: 9085.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DKFZp781I1140 / Production host: Escherichia coli (E. coli) / References: UniProt: Q7Z3L0, UniProt: Q14498*PLUS
#4: Protein DET1- and DDB1-associated protein 1 / Placenta cross-immune reaction antigen 1 / PCIA-1


Mass: 11724.102 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BW61

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Non-polymers , 3 types, 747 molecules

#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EF6 / N~1~-(3-chloro-1H-indol-7-yl)benzene-1,4-disulfonamide / Indisulam / Indisulam


Mass: 385.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12ClN3O4S2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antitumor, inhibitor, medication*YM
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 744 / 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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 2% (v:v) TacsimateTM, pH 5.0, 0.1 M sodium citrate tribasic dihydrate, pH 5.6, and 10-20% (w:v) polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→88.39 Å / Num. obs: 90574 / % possible obs: 99.8 % / Redundancy: 11.8 % / Biso Wilson estimate: 58.69 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.248 / Rpim(I) all: 0.076 / Rrim(I) all: 0.262 / Net I/σ(I): 6.1
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 11.7 % / Rmerge(I) obs: 3.598 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 4436 / CC1/2: 0.483 / % possible all: 98.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
RESOLVEphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→69.1 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.899 / SU R Cruickshank DPI: 0.242 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.252 / SU Rfree Blow DPI: 0.206 / SU Rfree Cruickshank DPI: 0.204
RfactorNum. reflection% reflectionSelection details
Rfree0.248 4576 5.06 %RANDOM
Rwork0.205 ---
obs0.207 90501 99.9 %-
Displacement parametersBiso max: 256.26 Å2 / Biso mean: 80.55 Å2 / Biso min: 35.01 Å2
Baniso -1Baniso -2Baniso -3
1-18.1585 Å20 Å20 Å2
2---8.8807 Å20 Å2
3----9.2778 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.3→69.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10808 0 36 744 11588
Biso mean--67.57 74.3 -
Num. residues----1386
LS refinement shellResolution: 2.3→2.31 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2398 84 4.64 %
Rwork0.2299 1727 -
all0.2303 1811 -
obs--95.92 %

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