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- EMDB-43413: The structure of LSD1-CoREST-HDAC1 in complex with KBTBD4IPR310de... -

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Entry
Database: EMDB / ID: EMD-43413
TitleThe structure of LSD1-CoREST-HDAC1 in complex with KBTBD4IPR310delinsTTYML
Map data
Sample
  • Complex: LHC-K4TTYML
    • Protein or peptide: Isoform 2 of 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 / NuRD complex / negative regulation of androgen receptor signaling pathway / regulation of cell fate specification / negative regulation of stem cell population maintenance / endoderm development / histone deacetylase activity, hydrolytic mechanism / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / histone deacetylase / regulation of stem cell differentiation / protein deacetylation / Regulation of MITF-M-dependent genes involved in apoptosis / STAT3 nuclear events downstream of ALK signaling / 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 / G1/S-Specific Transcription / Sin3-type complex / negative regulation of intrinsic apoptotic signaling pathway / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of stem cell population maintenance / E-box binding / histone methyltransferase complex / histone deacetylase complex / oligodendrocyte differentiation / RNA Polymerase I Transcription Initiation / positive regulation of oligodendrocyte differentiation / G0 and Early G1 / Regulation of MECP2 expression and activity / host-mediated suppression of viral transcription / hair follicle placode formation / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / RNA polymerase II core promoter sequence-specific DNA binding / core promoter sequence-specific DNA binding / heterochromatin / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / Nuclear events stimulated by ALK signaling in cancer / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / cellular response to platelet-derived growth factor stimulus / transcription repressor complex / negative regulation of canonical NF-kappaB signal transduction / positive regulation of smooth muscle cell proliferation / Transcriptional and post-translational regulation of MITF-M expression and activity / negative regulation of cell migration / SUMOylation of chromatin organization proteins / Regulation of PTEN gene transcription / erythrocyte differentiation / transcription corepressor binding / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of endogenous retroelements by KRAB-ZFP proteins / hippocampus development / Deactivation of the beta-catenin transactivating complex / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / circadian regulation of gene expression / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / negative regulation of transforming growth factor beta receptor signaling pathway / negative regulation of canonical Wnt signaling pathway / Formation of the beta-catenin:TCF transactivating complex / 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 / p53 binding / transcription corepressor activity / heterochromatin formation / Factors involved in megakaryocyte development and platelet production / chromatin organization / transcription regulator complex / DNA-binding transcription factor binding / Estrogen-dependent gene expression / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling
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: 3.3 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 16, 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_43413.png

Downloads & links

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Map

FileDownload / File: emd_43413.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.133
Minimum - Maximum-1.1690627 - 1.5509912
Average (Standard dev.)-0.00011005409 (±0.024694104)
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_43413_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43413_half_map_2.map
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Sample components

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Entire : LHC-K4TTYML

EntireName: LHC-K4TTYML
Components
  • Complex: LHC-K4TTYML
    • Protein or peptide: Isoform 2 of 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-K4TTYML

SupramoleculeName: LHC-K4TTYML / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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: 60.213977 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 GSTTYMLRMW KCN NATVDW EWCAPLPRDR LQHTLVSVPG KDAIYSLGGK TLQDTLSNAV IYYRVGDNVW TETTQLEVAV SGAAGANLNG IIYL LGGEE NDLDFFTKPS RLIQCFDTET DKCHVKPYVL PFAGRMHAAV HKDLVFIVAE GDSLVCYNPL LDSFTRLCLP EAWSS APSL WKIASCNGSI YVFRDRYKKG DANTYKLDPA TSAVTVTRGI KVLLTNLQFV LA

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: Homo sapiens (human)
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: 53.401352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPAMVEKGPE VSGKRRGRNN AAASASAAAA SAAASAACAS PAATAASGAA ASSASAAAAS AAAAPNNGQN KSLAAAAPNG NSSSNSWEE GSSGSSSDEE HGGGGMRVGP QYQAVVPDFD PAKLARRSQE RDNLGMLVWS PNQNLSEAKL DEYIAIAKEK H GYNMEQAL ...String:
MPAMVEKGPE VSGKRRGRNN AAASASAAAA SAAASAACAS PAATAASGAA ASSASAAAAS AAAAPNNGQN KSLAAAAPNG NSSSNSWEE GSSGSSSDEE HGGGGMRVGP QYQAVVPDFD PAKLARRSQE RDNLGMLVWS PNQNLSEAKL DEYIAIAKEK H GYNMEQAL GMLFWHKHNI EKSLADLPNF TPFPDEWTVE DKVLFEQAFS FHGKTFHRIQ QMLPDKSIAS LVKFYYSWKK TR TKTSVMD RHARKQKRER EESEDELEEA NGNNPIDIEV DQNKESKKEV PPTETVPQVK KEKHSTQAKN RAKRKPPKGM FLS QEDVEA VSANATAATT VLRQLDMELV SVKRQIQNIK QTNSALKEKL DGGIEPYRLP EVIQKCNARW TTEEQLLAVQ AIRK YGRDF QAISDVIGNK SVVQVKNFFV NYRRRFNIDE VLQEWEAEHG KEETNGPSNQ KPVKSPDNSI KMPEEEDEAP VLDVR 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 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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 825583
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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