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- PDB-9dtg: The cryo-EM structure of apo KBTBD4 -

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Basic information

Entry
Database: PDB / ID: 9dtg
TitleThe cryo-EM structure of apo KBTBD4
ComponentsIsoform 2 of Kelch repeat and BTB domain-containing protein 4
KeywordsLIGASE / molecular glue / targeted protein degradation / E3 ligase / transcription and tranlation
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.83 Å
AuthorsXie, X. / Mao, H. / Liau, B. / Zheng, N.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2 of Kelch repeat and BTB domain-containing protein 4
B: Isoform 2 of Kelch repeat and BTB domain-containing protein 4


Theoretical massNumber of molelcules
Total (without water)119,9432
Polymers119,9432
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Isoform 2 of Kelch repeat and BTB domain-containing protein 4 / BTB and kelch domain-containing protein 4


Mass: 59971.711 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KBTBD4, BKLHD4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NVX7
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: KBTBD4 dimer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 550442 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028244
ELECTRON MICROSCOPYf_angle_d0.60811192
ELECTRON MICROSCOPYf_dihedral_angle_d3.9351106
ELECTRON MICROSCOPYf_chiral_restr0.0421267
ELECTRON MICROSCOPYf_plane_restr0.0051438

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