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- EMDB-47155: The cryo-EM structure of apo KBTBD4 -

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Basic information

Entry
Database: EMDB / ID: EMD-47155
TitleThe cryo-EM structure of apo KBTBD4
Map data
Sample
  • Complex: KBTBD4 dimer
    • Protein or peptide: Isoform 2 of Kelch repeat and BTB domain-containing protein 4
Keywordsmolecular glue / targeted protein degradation / E3 ligase / transcription and tranlation / LIGASE
Function / homology
Function and homology information


Kelch repeat and BTB domain-containing protein 4 / KBTBD4, BTB/POZ domain / KBTBD4, BACK domain / Kelch repeat type 2 / Kelch motif / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch-type beta propeller ...Kelch repeat and BTB domain-containing protein 4 / KBTBD4, BTB/POZ domain / KBTBD4, BACK domain / Kelch repeat type 2 / Kelch motif / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily
Similarity search - Domain/homology
Kelch repeat and BTB domain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.83 Å
AuthorsXie X / Mao H / Liau B / Zheng N
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2025
Title: UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.
Authors: Megan J R Yeo / Olivia Zhang / Xiaowen Xie / Eunju Nam / N Connor Payne / Pallavi M Gosavi / Hui Si Kwok / Irtiza Iram / Ceejay Lee / Jiaming Li / Nicholas J Chen / Khanh Nguyen / Hanjie ...Authors: Megan J R Yeo / Olivia Zhang / Xiaowen Xie / Eunju Nam / N Connor Payne / Pallavi M Gosavi / Hui Si Kwok / Irtiza Iram / Ceejay Lee / Jiaming Li / Nicholas J Chen / Khanh Nguyen / Hanjie Jiang / Zhipeng A Wang / Kwangwoon Lee / Haibin Mao / Stefan A Harry / Idris A Barakat / Mariko Takahashi / Amanda L Waterbury / Marco Barone / Andrea Mattevi / Steven A Carr / Namrata D Udeshi / Liron Bar-Peled / Philip A Cole / Ralph Mazitschek / Brian B Liau / Ning Zheng /
Abstract: UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal. By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the ...UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal. By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1-CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3-neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST-HDAC1/2-KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.
History
DepositionSep 30, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateMar 19, 2025-
Current statusMar 19, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47155.png

Downloads & links

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Map

FileDownload / File: emd_47155.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 384 pix.
= 339.84 Å		0.89 Å/pix.
x 384 pix.
= 339.84 Å		0.89 Å/pix.
x 384 pix.
= 339.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.885 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.218
Minimum - Maximum-1.4566303 - 2.1862109
Average (Standard dev.)0.0000048627703 (±0.02344464)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 339.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_47155_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_47155_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : KBTBD4 dimer

EntireName: KBTBD4 dimer
Components
  • Complex: KBTBD4 dimer
    • Protein or peptide: Isoform 2 of Kelch repeat and BTB domain-containing protein 4

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Supramolecule #1: KBTBD4 dimer

SupramoleculeName: KBTBD4 dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 2 of Kelch repeat and BTB domain-containing protein 4

MacromoleculeName: Isoform 2 of Kelch repeat and BTB domain-containing protein 4
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.971711 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MKGGNADSWQ REKLASMESP EEPGASMDEN YFVNYTFKDR SHSGRVAQGI MKLCLEEELF ADVTISVEGR EFQLHRLVLS AQSCFFRSM FTSNLKEAHN RVIVLQDVSE SVFQLLVDYI YHGTVKLRAE ELQEIYEVSD MYQLTSLFEE CSRFLARTVQ V GNCLQVMW ...String:
MKGGNADSWQ REKLASMESP EEPGASMDEN YFVNYTFKDR SHSGRVAQGI MKLCLEEELF ADVTISVEGR EFQLHRLVLS AQSCFFRSM FTSNLKEAHN RVIVLQDVSE SVFQLLVDYI YHGTVKLRAE ELQEIYEVSD MYQLTSLFEE CSRFLARTVQ V GNCLQVMW LADRHSDPEL YTAAKHCAKT HLAQLQNTEE FLHLPHRLLT DIISDGVPCS QNPTEAIEAW INFNKEEREA FA ESLRTSL KEIGENVHIY LIGKESSRTH SLAVSLHCAE DDSISVSGQN SLCHQITAAC KHGGDLYVVG GSIPRRMWKC NNA TVDWEW CAPLPRDRLQ HTLVSVPGKD AIYSLGGKTL QDTLSNAVIY YRVGDNVWTE TTQLEVAVSG AAGANLNGII YLLG GEEND LDFFTKPSRL IQCFDTETDK CHVKPYVLPF AGRMHAAVHK DLVFIVAEGD SLVCYNPLLD SFTRLCLPEA WSSAP SLWK IASCNGSIYV FRDRYKKGDA NTYKLDPATS AVTVTRGIKV LLTNLQFVLA

UniProtKB: Kelch repeat and BTB domain-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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.83 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 550442
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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