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- EMDB-47156: The structure of HDAC2-CoREST in complex with KBTBD4R313PRR mutant -

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Basic information

Entry
Database: EMDB / ID: EMD-47156
TitleThe structure of HDAC2-CoREST in complex with KBTBD4R313PRR mutant
Map data
Sample
  • Complex: LHC-KBTBD4PRRmutant
    • Protein or peptide: Histone deacetylase 2
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 4
    • Protein or peptide: REST corepressor 1
  • Ligand: INOSITOL HEXAKISPHOSPHATE
Keywordsprotein degradation / E3 ligase / Neo-substrate / cancer mutation / LIGASE
Function / homology
Function and homology information


positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol ...positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / negative regulation of stem cell population maintenance / histone deacetylase activity, hydrolytic mechanism / ESC/E(Z) complex / histone deacetylase / regulation of stem cell differentiation / cardiac muscle hypertrophy / cellular response to dopamine / STAT3 nuclear events downstream of ALK signaling / DNA repair complex / response to caffeine / 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 / Notch-HLH transcription pathway / Sin3-type complex / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of stem cell population maintenance / dendrite development / histone methyltransferase complex / response to amyloid-beta / histone deacetylase complex / RNA Polymerase I Transcription Initiation / positive regulation of oligodendrocyte differentiation / positive regulation of proteolysis / Regulation of MECP2 expression and activity / progesterone receptor signaling pathway / hair follicle placode formation / response to hyperoxia / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to transforming growth factor beta stimulus / positive regulation of epithelial to mesenchymal transition / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / cellular response to retinoic acid / heat shock protein binding / transcription repressor complex / SUMOylation of chromatin organization proteins / negative regulation of cell migration / response to amphetamine / Regulation of PTEN gene transcription / erythrocyte differentiation / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription coregulator binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / response to nicotine / response to cocaine / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / circadian regulation of gene expression / negative regulation of transforming growth factor beta receptor signaling pathway / NoRC negatively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / protein modification process / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / transcription corepressor activity / heterochromatin formation / negative regulation of neuron projection development / cellular response to heat / Factors involved in megakaryocyte development and platelet production / chromatin organization / histone binding / response to lipopolysaccharide / transcription regulator complex / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of gene expression / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / chromatin binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin
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 2 / Kelch repeat and BTB domain-containing protein 4 / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.87 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
DepositionOct 1, 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_47156.png

Downloads & links

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Map

FileDownload / File: emd_47156.map.gz / Format: CCP4 / Size: 216 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.)
0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.28
Minimum - Maximum-1.8605399 - 2.6704085
Average (Standard dev.)-0.00023954693 (±0.03821574)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 322.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_47156_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_47156_half_map_2.map
Projections & Slices
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Sample components

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Entire : LHC-KBTBD4PRRmutant

EntireName: LHC-KBTBD4PRRmutant
Components
  • Complex: LHC-KBTBD4PRRmutant
    • Protein or peptide: Histone deacetylase 2
    • Protein or peptide: Kelch repeat and BTB domain-containing protein 4
    • Protein or peptide: REST corepressor 1
  • 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: Histone deacetylase 2

MacromoleculeName: Histone deacetylase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: histone deacetylase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.311961 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: AYSQGGGKKK VCYYYDGDIG NYYYGQGHPM KPHRIRMTHN LLLNYGLYRK MEIYRPHKAT AEEMTKYHSD EYIKFLRSIR PDNMSEYSK QMQRFNVGED CPVFDGLFEF CQLSTGGSVA GAVKLNRQQT DMAVNWAGGL HHAKKSEASG FCYVNDIVLA I LELLKYHQ ...String:
AYSQGGGKKK VCYYYDGDIG NYYYGQGHPM KPHRIRMTHN LLLNYGLYRK MEIYRPHKAT AEEMTKYHSD EYIKFLRSIR PDNMSEYSK QMQRFNVGED CPVFDGLFEF CQLSTGGSVA GAVKLNRQQT DMAVNWAGGL HHAKKSEASG FCYVNDIVLA I LELLKYHQ RVLYIDIDIH HGDGVEEAFY TTDRVMTVSF HKYGEYFPGT GDLRDIGAGK GKYYAVNFPM RDGIDDESYG QI FKPIISK VMEMYQPSAV VLQCGADSLS GDRLGCFNLT VKGHAKCVEV VKTFNLPLLM LGGGGYTIRN VARCWTYETA VAL DCEIPN ELPYNDYFEY FGPDFKLHIS PSNMTNQNTP EYMEKIKQRL FENLRMLPHA PGVQMQAIPE DAVHEDSGDE DGED PDKRI SIRASDKRIA CDEEFSDSED EGEGGRRNVA DHKKGAKKAR IEEDKKETED KKTDVKEEDK SKDNSGEKTD TKGTK SEQL SNP

UniProtKB: Histone deacetylase 2

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

MacromoleculeName: Kelch repeat and BTB domain-containing protein 4 / type: protein_or_peptide / ID: 2 / 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 #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: Homo sapiens (human)
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: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 4 / 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 KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 300 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.87 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 700385
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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