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- EMDB-43487: The structure of LSD1-CoREST-HDAC1 in complex with KBTBD4R313PRR ... -

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Basic information

Entry
Database: EMDB / ID: EMD-43487
TitleThe structure of LSD1-CoREST-HDAC1 in complex with KBTBD4R313PRR mutant
Map data
Sample
  • Complex: LHC-KBTBD4PRRmutant
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 4
    • Protein or peptide: Histone deacetylase 1
    • Protein or peptide: REST corepressor 1
  • Ligand: ZINC ION
  • Ligand: INOSITOL HEXAKISPHOSPHATE
Keywordsprotein degradation / E3 ligase / Neo-substrate / cancer mutation / LIGASE
Function / homology
Function and homology information


Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation ...Loss of MECP2 binding ability to 5mC-DNA / Krueppel-associated box domain binding / Repression of WNT target genes / MECP2 regulates transcription of neuronal ligands / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation / negative regulation of androgen receptor signaling pathway / NuRD complex / regulation of cell fate specification / endoderm development / negative regulation of stem cell population maintenance / histone H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / histone H4K12 deacetylase activity, hydrolytic mechanism / protein deacetylation / Regulation of MITF-M-dependent genes involved in apoptosis / histone deacetylase / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / histone H3K9 deacetylase activity, hydrolytic mechanism / Transcription of E2F targets under negative control by DREAM complex / DNA repair complex / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / embryonic digit morphogenesis / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / DNA methylation-dependent constitutive heterochromatin formation / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / Sin3-type complex / E-box binding / G1/S-Specific Transcription / eyelid development in camera-type eye / positive regulation of stem cell population maintenance / negative regulation of intrinsic apoptotic signaling pathway / oligodendrocyte differentiation / odontogenesis of dentin-containing tooth / RNA Polymerase I Transcription Initiation / histone deacetylase complex / positive regulation of oligodendrocyte differentiation / Regulation of MECP2 expression and activity / G0 and Early G1 / negative regulation by host of viral transcription / hair follicle placode formation / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / heterochromatin / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / core promoter sequence-specific DNA binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / RNA polymerase II core promoter sequence-specific DNA binding / Nuclear events stimulated by ALK signaling in cancer / MECP2 regulates neuronal receptors and channels / negative regulation of canonical NF-kappaB signal transduction / Regulation of TP53 Activity through Acetylation / cellular response to platelet-derived growth factor stimulus / transcription repressor complex / Transcriptional and post-translational regulation of MITF-M expression and activity / SUMOylation of chromatin organization proteins / erythrocyte differentiation / negative regulation of cell migration / hippocampus development / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of PTEN gene transcription / transcription corepressor binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / positive regulation of smooth muscle cell proliferation / Deactivation of the beta-catenin transactivating complex / promoter-specific chromatin binding / negative regulation of transforming growth factor beta receptor signaling pathway / Downregulation of SMAD2/3:SMAD4 transcriptional activity / circadian regulation of gene expression / Formation of the beta-catenin:TCF transactivating complex / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / negative regulation of canonical Wnt signaling pathway / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / neuron differentiation / transcription corepressor activity / p53 binding / heterochromatin formation / chromatin organization / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex
Similarity search - Function
Kelch repeat and BTB domain-containing protein 4 / KBTBD4, BTB/POZ domain / KBTBD4, BACK domain / Kelch repeat type 2 / Kelch motif / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain ...Kelch repeat and BTB domain-containing protein 4 / KBTBD4, BTB/POZ domain / KBTBD4, BACK domain / Kelch repeat type 2 / Kelch motif / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone deacetylase / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / SANT domain profile. / SANT domain / Kelch-type beta propeller / Myb-like DNA-binding domain / : / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / BTB/POZ domain / BTB domain profile. / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / Homeobox-like domain superfamily
Similarity search - Domain/homology
Histone deacetylase 1 / Kelch repeat and BTB domain-containing protein 4 / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsXie X / Liau B / Zheng N
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2025
Title: Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations.
Authors: Xiaowen Xie / Olivia Zhang / Megan J R Yeo / Ceejay Lee / Ran Tao / Stefan A Harry / N Connor Payne / Eunju Nam / Leena Paul / Yiran Li / Hui Si Kwok / Hanjie Jiang / Haibin Mao / Jennifer L ...Authors: Xiaowen Xie / Olivia Zhang / Megan J R Yeo / Ceejay Lee / Ran Tao / Stefan A Harry / N Connor Payne / Eunju Nam / Leena Paul / Yiran Li / Hui Si Kwok / Hanjie Jiang / Haibin Mao / Jennifer L Hadley / Hong Lin / Melissa Batts / Pallavi M Gosavi / Vincenzo D'Angiolella / Philip A Cole / Ralph Mazitschek / Paul A Northcott / Ning Zheng / Brian B Liau /
Abstract: Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated ...Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma, the most common embryonal brain tumour in children. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3-neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions.
History
DepositionJan 22, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateJun 11, 2025-
Current statusJun 11, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43487.png

Downloads & links

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Map

FileDownload / File: emd_43487.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 440 pix.
= 389.4 Å		0.89 Å/pix.
x 440 pix.
= 389.4 Å		0.89 Å/pix.
x 440 pix.
= 389.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.885 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.216
Minimum - Maximum-0.47657642 - 0.8551172
Average (Standard dev.)-0.0001443313 (±0.01570607)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-29-29-29
Dimensions440440440
Spacing440440440
CellA=B=C: 389.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43487_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

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Half map: #2

Fileemd_43487_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : LHC-KBTBD4PRRmutant

EntireName: LHC-KBTBD4PRRmutant
Components
  • Complex: LHC-KBTBD4PRRmutant
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 4
    • Protein or peptide: Histone deacetylase 1
    • Protein or peptide: REST corepressor 1
  • Ligand: ZINC ION
  • Ligand: INOSITOL HEXAKISPHOSPHATE

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Supramolecule #1: LHC-KBTBD4PRRmutant

SupramoleculeName: LHC-KBTBD4PRRmutant / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: 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: 58.463059 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MESPEEPGAS MDENYFVNYT FKDRSHSGRV AQGIMKLCLE EELFADVTIS VEGREFQLHR LVLSAQSCFF RSMFTSNLKE AHNRVIVLQ DVSESVFQLL VDYIYHGTVK LRAEELQEIY EVSDMYQLTS LFEECSRFLA RTVQVGNCLQ VMWLADRHSD P ELYTAAKH ...String:
MESPEEPGAS MDENYFVNYT FKDRSHSGRV AQGIMKLCLE EELFADVTIS VEGREFQLHR LVLSAQSCFF RSMFTSNLKE AHNRVIVLQ DVSESVFQLL VDYIYHGTVK LRAEELQEIY EVSDMYQLTS LFEECSRFLA RTVQVGNCLQ VMWLADRHSD P ELYTAAKH CAKTHLAQLQ NTEEFLHLPH RLLTDIISDG VPCSQNPTEA IEAWINFNKE EREAFAESLR TSLKEIGENV HI YLIGKES SRTHSLAVSL HCAEDDSISV SGQNSLCHQI TAACKHGGDL YVVGGSIPRP RRMWKCNNAT VDWEWCAPLP RDR LQHTLV SVPGKDAIYS LGGKTLQDTL SNAVIYYRVG DNVWTETTQL EVAVSGAAGA NLNGIIYLLG GEENDLDFFT KPSR LIQCF DTETDKCHVK PYVLPFAGRM HAAVHKDLVF IVAEGDSLVC YNPLLDSFTR LCLPEAWSSA PSLWKIASCN GSIYV FRDR YKKGDANTYK LDPATSAVTV TRGIKVLLTN LQFVLA

UniProtKB: Kelch repeat and BTB domain-containing protein 4

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Macromolecule #2: Histone deacetylase 1

MacromoleculeName: Histone deacetylase 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: histone deacetylase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.178906 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MAQTQGTRRK VCYYYDGDVG NYYYGQGHPM KPHRIRMTHN LLLNYGLYRK MEIYRPHKAN AEEMTKYHSD DYIKFLRSIR PDNMSEYSK QMQRFNVGED CPVFDGLFEF CQLSTGGSVA SAVKLNKQQT DIAVNWAGGL HHAKKSEASG FCYVNDIVLA I LELLKYHQ ...String:
MAQTQGTRRK VCYYYDGDVG NYYYGQGHPM KPHRIRMTHN LLLNYGLYRK MEIYRPHKAN AEEMTKYHSD DYIKFLRSIR PDNMSEYSK QMQRFNVGED CPVFDGLFEF CQLSTGGSVA SAVKLNKQQT DIAVNWAGGL HHAKKSEASG FCYVNDIVLA I LELLKYHQ RVLYIDIDIH HGDGVEEAFY TTDRVMTVSF HKYGEYFPGT GDLRDIGAGK GKYYAVNYPL RDGIDDESYE AI FKPVMSK VMEMFQPSAV VLQCGSDSLS GDRLGCFNLT IKGHAKCVEF VKSFNLPMLM LGGGGYTIRN VARCWTYETA VAL DTEIPN ELPYNDYFEY FGPDFKLHIS PSNMTNQNTN EYLEKIKQRL FENLRMLPHA PGVQMQAIPE DAIPEESGDE DEDD PDKRI SICSSDKRIA CEEEFSDSEE EGEGGRKNSS NFKKAKRVKT EDEKEKDPEE KKEVTEEEKT KEEKPEAKGV KEEVK LA

UniProtKB: Histone deacetylase 1

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Macromolecule #3: REST corepressor 1

MacromoleculeName: REST corepressor 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.974441 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSWEEGSSGS SSDEEHGGGG MRVGPQYQAV VPDFDPAKLA RRSQERDNLG MLVWSPNQNL SEAKLDEYIA IAKEKHGYNM EQALGMLFW HKHNIEKSLA DLPNFTPFPD EWTVEDKVLF EQAFSFHGKT FHRIQQMLPD KSIASLVKFY YSWKKTRTKT S VMDRHARK ...String:
MSWEEGSSGS SSDEEHGGGG MRVGPQYQAV VPDFDPAKLA RRSQERDNLG MLVWSPNQNL SEAKLDEYIA IAKEKHGYNM EQALGMLFW HKHNIEKSLA DLPNFTPFPD EWTVEDKVLF EQAFSFHGKT FHRIQQMLPD KSIASLVKFY YSWKKTRTKT S VMDRHARK QKREREESED ELEEANGNNP IDIEVDQNKE SKKEVPPTET VPQVKKEKHS TQAKNRAKRK PPKGMFLSQE DV EAVSANA TAATTVLRQL DMELVSVKRQ IQNIKQTNSA LKEKLDGGIE PYRLPEVIQK CNARWTTEEQ LLAVQAIRKY GRD FQAISD VIGNKSVVQV KNFFVNYRRR FNIDEVLQEW EAEHGKEETN GPSNQKPVKS PDNSIKMPEE EDEAPVLDVR YASA S

UniProtKB: REST corepressor 1

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.0 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

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 110048
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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