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- EMDB-17172: Ternary structure of intramolecular bivalent glue degrader IBG1 b... -

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Entry
Database: EMDB / ID: EMD-17172
TitleTernary structure of intramolecular bivalent glue degrader IBG1 bound to BRD4 and DCAF16:DDB1deltaBPB
Map dataSharpened map
Sample
  • Complex: Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 and DDB1deltaBPB
    • Complex: DCAF16:DDB1deltaBPB E3 receptor:adaptor complex
      • Protein or peptide: DDB1deltaBPB
      • Protein or peptide: DCAF16
    • Protein or peptide: BRD4 Tandem Bromodomains
KeywordsBromodomain / BET protein / DCAF16 / Bivalent glue / Targeted protein degradation / TPD / TRANSCRIPTION
Function / homology
Function and homology information


positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / 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 ...positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / 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 / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / viral release from host cell / P-TEFb complex binding / negative regulation by host of viral transcription / ectopic germ cell programmed cell death / proteasomal protein catabolic process / positive regulation of viral genome replication / positive regulation of T-helper 17 cell lineage commitment / positive regulation of gluconeogenesis / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / DNA Damage Recognition in GG-NER / lysine-acetylated histone binding / regulation of circadian rhythm / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / 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 / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / p53 binding / protein-macromolecule adaptor activity / chromosome / Neddylation / site of double-strand break / regulation of inflammatory response / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / chromosome, telomeric region / damaged DNA binding / transcription coactivator activity / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / DNA repair / apoptotic process / DNA damage response / chromatin binding / protein-containing complex binding / chromatin / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
DDB1- and CUL4-associated factor 16 / DDB1- and CUL4-associated factor 16 / 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 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. ...DDB1- and CUL4-associated factor 16 / DDB1- and CUL4-associated factor 16 / 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 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Bromodomain-containing protein 4 / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 16
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.77 Å
AuthorsCowan AD / Sundaramoorthy R / Nakasone MA / Ciulli A
Funding supportEuropean Union, Switzerland, United Kingdom, Austria, 9 items
OrganizationGrant numberCountry
H2020 Marie Curie Actions of the European Commission101024945European Union
European Research Council (ERC)ERC-2012-StG-311460European Union
Innovative Medicines Initiative875510 Switzerland
Wellcome Trust223816/Z/21/Z United Kingdom
Medical Research Council (MRC, United Kingdom)4050845509 United Kingdom
European Research Council (ERC)851478European Union
Austrian Science FundP32125 Austria
Austrian Science FundP31690 Austria
Austrian Science FundP7909 Austria
Citation
Journal: Nature / Year: 2024
Title: Targeted protein degradation via intramolecular bivalent glues.
Authors: Oliver Hsia / Matthias Hinterndorfer / Angus D Cowan / Kentaro Iso / Tasuku Ishida / Ramasubramanian Sundaramoorthy / Mark A Nakasone / Hana Imrichova / Caroline Schätz / Andrea Rukavina / ...Authors: Oliver Hsia / Matthias Hinterndorfer / Angus D Cowan / Kentaro Iso / Tasuku Ishida / Ramasubramanian Sundaramoorthy / Mark A Nakasone / Hana Imrichova / Caroline Schätz / Andrea Rukavina / Koraljka Husnjak / Martin Wegner / Alejandro Correa-Sáez / Conner Craigon / Ryan Casement / Chiara Maniaci / Andrea Testa / Manuel Kaulich / Ivan Dikic / Georg E Winter / Alessio Ciulli /
Abstract: Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal ...Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)-bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change 'glues' BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4-IBG1-DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
#1: Journal: Biorxiv / Year: 2023
Title: Targeted protein degradation via intramolecular bivalent glues
Authors: Hsia O / Hinterndorfer M / Cowan AD / Iso K / Ishida I / Sundaramoorthy R / Nakasone MA / Imrichova H / Schatz C / Rukvina A / Husnjak K / Wegner M / Correa-Saez A / Craigon C / Casement R / ...Authors: Hsia O / Hinterndorfer M / Cowan AD / Iso K / Ishida I / Sundaramoorthy R / Nakasone MA / Imrichova H / Schatz C / Rukvina A / Husnjak K / Wegner M / Correa-Saez A / Craigon C / Casement R / Maniaci C / Testa A / Kaulich M / Dikic I / Winter GE / Ciulli A
History
DepositionApr 20, 2023-
Header (metadata) releaseMay 17, 2023-
Map releaseMay 17, 2023-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17172.png

Downloads & links

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Map

FileDownload / File: emd_17172.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Voxel sizeX=Y=Z: 0.74 Å
Density
Contour LevelBy AUTHOR: 0.17
Minimum - Maximum-0.9737328 - 1.2537807
Average (Standard dev.)0.0000097455395 (±0.03627334)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 239.76001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_17172_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Unsharpened map

Fileemd_17172_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_17172_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: Half map B

Fileemd_17172_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 a...

EntireName: Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 and DDB1deltaBPB
Components
  • Complex: Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 and DDB1deltaBPB
    • Complex: DCAF16:DDB1deltaBPB E3 receptor:adaptor complex
      • Protein or peptide: DDB1deltaBPB
      • Protein or peptide: DCAF16
    • Protein or peptide: BRD4 Tandem Bromodomains

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Supramolecule #1: Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 a...

SupramoleculeName: Ternary complex of BRD4 tandem bromodomains, compound 1, DCAF16 and DDB1deltaBPB
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 118 KDa

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Supramolecule #2: DCAF16:DDB1deltaBPB E3 receptor:adaptor complex

SupramoleculeName: DCAF16:DDB1deltaBPB E3 receptor:adaptor complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DDB1deltaBPB

MacromoleculeName: DDB1deltaBPB / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL YGCQAPTICF VYQDPQGRHV KTYEVSLREK EFNKGPWKQE NVEAEASMVI AVPEPFGGAI IIGQESITYH NGDKYLAIAP PIIKQSTIVC HNRVDPNGSR YLLGDMEGRL FMLLLEKEEQ MDGTVTLKDL RVELLGETSI AECLTYLDNG VVFVGSRLGD SQLVKLNVDS NEQGSYVVAM ETFTNLGPIV DMCVVDLERQ GQGQLVTCSG AFKEGSLRII RNGIGGNGNS GEIQKLHIRT VPLYESPRKI CYQEVSQCFG VLSSRIEVQD TSGGTTALRP SASTQALSSS VSSSKLFSSS TAPHETSFGE EVEVHNLLII DQHTFEVLHA HQFLQNEYAL SLVSCKLGKD PNTYFIVGTA MVYPEEAEPK QGRIVVFQYS DGKLQTVAEK EVKGAVYSMV EFNGKLLASI NSTVRLYEWT TEKELRTECN HYNNIMALYL KTKGDFILVG DLMRSVLLLA YKPMEGNFEE IARDFNPNWM SAVEILDDDN FLGAENAFNL FVCQKDSAAT TDEERQHLQE VGLFHLGEFV NVFCHGSLVM QNLGETSTPT QGSVLFGTVN GMIGLVTSLS ESWYNLLLDM QNRLNKVIKS VGKIEHSFWR SFHTERKTEP ATGFIDGDLI ESFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1

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Macromolecule #2: DCAF16

MacromoleculeName: DCAF16 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GGMGPRNPSP DHLSESESEE EENISYLNES SGEEWDSSEE EDSMVPNLSP LESLAWQVKC LLKYSTTWKP LNPNSWLYHA KLLDPSTPVH ILREIGLRLS HCSHCVPKLE PIPEWPPLAS CGVPPFQKPL TSPSRLSRDH ATLNGALQFA TKQLSRTLSR ATPIPEYLKQ ...String:
GGMGPRNPSP DHLSESESEE EENISYLNES SGEEWDSSEE EDSMVPNLSP LESLAWQVKC LLKYSTTWKP LNPNSWLYHA KLLDPSTPVH ILREIGLRLS HCSHCVPKLE PIPEWPPLAS CGVPPFQKPL TSPSRLSRDH ATLNGALQFA TKQLSRTLSR ATPIPEYLKQ IPNSCVSGCC CGWLTKTVKE TTRTEPINTT YSYTDFQKAV NKLLTASL

UniProtKB: DDB1- and CUL4-associated factor 16

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Macromolecule #3: BRD4 Tandem Bromodomains

MacromoleculeName: BRD4 Tandem Bromodomains / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GSTNPPPPET SNPNKPKRQT NQLQYLLRVV LKTLWKHQFA WPFQQPVDAV KLNLPDYYKI IKTPMDMGTI KKRLENNYYW NAQECIQDFN TMFTNCYIYN KPGDDIVLMA EALEKLFLQK INELPTEETE IMIVQAKGRG RGRKETGTAK PGVSTVPNTT QASTPPQTQT ...String:
GSTNPPPPET SNPNKPKRQT NQLQYLLRVV LKTLWKHQFA WPFQQPVDAV KLNLPDYYKI IKTPMDMGTI KKRLENNYYW NAQECIQDFN TMFTNCYIYN KPGDDIVLMA EALEKLFLQK INELPTEETE IMIVQAKGRG RGRKETGTAK PGVSTVPNTT QASTPPQTQT PQPNPPPVQA TPHPFPAVTP DLIVQTPVMT VVPPQPLQTP PPVPPQPQPP PAPAPQPVQS HPPIIAATPQ PVKTKKGVKR KADTTTPTTI DPIHEPPSLP PEPKTTKLGQ RRESSRPVKP PKKDVPDSQQ HPAPEKSSKV SEQLKCCSGI LKEMFAKKHA AYAWPFYKPV DVEALGLHDY CDIIKHPMDM STIKSKLEAR EYRDAQEFGA DVRLMFSNCY KYNPPDHEVV AMARKLQDVF EMRFAKMPD

UniProtKB: Bromodomain-containing protein 4

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.8 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
50.0 mMNaClsodium chloride
0.5 mMC9H15O6PTCEP
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Details: Current 35 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Details: 3.5 uL complex was dispensed onto the grid, allowed to disperse for 10 s, blotted for 3.5 s using blot force 3, then plunged into liquid ethane.
DetailsThe components were co-incubated then loaded onto a 10/300 Superdex 200 gl column and the fraction corresponding to the complex was collected and concentrated to 0.8 mg/mL

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 2075 / Average exposure time: 2.0 sec. / Average electron dose: 12.7 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 190000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.2 µm / Nominal defocus min: 1.7 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.2.1) / Number images used: 192014
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.2.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChainDetails

6ud7

chain_id: B, source_name: PDB, initial_model_type: experimental model

3mxf

chain_id: A, source_name: PDB, initial_model_type: experimental model

6duv

chain_id: A, source_name: PDB, initial_model_type: experimental model
source_name: Other, initial_model_type: otherDCAF16 model was derived from both colabfold and model-angelo
Output model

PDB-8ov6:
Ternary structure of intramolecular bivalent glue degrader IBG1 bound to BRD4 and DCAF16:DDB1deltaBPB

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