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- PDB-9dtq: The structure of HDAC2-CoREST in complex with KBTBD4R313PRR mutant -

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Basic information

Entry
Database: PDB / ID: 9dtq
TitleThe structure of HDAC2-CoREST in complex with KBTBD4R313PRR mutant
Components
  • Histone deacetylase 2
  • Kelch repeat and BTB domain-containing protein 4
  • REST corepressor 1
KeywordsLIGASE / protein degradation / E3 ligase / Neo-substrate / cancer mutation
Function / homology
Function and homology information


positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation / negative regulation of MHC class II biosynthetic process ...positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / fungiform papilla formation / negative regulation of MHC class II biosynthetic process / behavioral response to ethanol / positive regulation of interleukin-1 production / NuRD complex / regulation of cell fate specification / negative regulation of transcription by competitive promoter binding / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of stem cell population maintenance / histone H4K16 deacetylase activity, hydrolytic mechanism / ESC/E(Z) complex / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / histone H4K12 deacetylase activity, hydrolytic mechanism / histone deacetylase / regulation of stem cell differentiation / cellular response to dopamine / cardiac muscle hypertrophy / STAT3 nuclear events downstream of ALK signaling / histone H3K9 deacetylase activity, hydrolytic mechanism / 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 / positive regulation of stem cell population maintenance / dendrite development / odontogenesis of dentin-containing tooth / response to amyloid-beta / positive regulation of proteolysis / RNA Polymerase I Transcription Initiation / histone deacetylase complex / positive regulation of oligodendrocyte differentiation / Regulation of MECP2 expression and activity / positive regulation of collagen biosynthetic process / hair follicle placode formation / response to hyperoxia / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / progesterone receptor signaling pathway / positive regulation of epithelial to mesenchymal transition / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / MECP2 regulates neuronal receptors and channels / cellular response to transforming growth factor beta stimulus / cellular response to retinoic acid / Regulation of TP53 Activity through Acetylation / heat shock protein binding / transcription repressor complex / response to amphetamine / SUMOylation of chromatin organization proteins / erythrocyte differentiation / negative regulation of cell migration / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of PTEN gene transcription / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / negative regulation of DNA-binding transcription factor activity / response to nicotine / promoter-specific chromatin binding / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / response to cocaine / NoRC negatively regulates rRNA expression / protein modification process / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / transcription corepressor activity / positive regulation of tumor necrosis factor production / heterochromatin formation / chromatin organization / negative regulation of neuron projection development / Factors involved in megakaryocyte development and platelet production / cellular response to heat / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / response to lipopolysaccharide / histone binding / Potential therapeutics for SARS / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus
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
INOSITOL HEXAKISPHOSPHATE / Histone deacetylase 2 / Kelch repeat and BTB domain-containing protein 4 / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.87 Å
AuthorsXie, X. / Liau, B. / Zheng, N.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 11, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone deacetylase 2
B: Kelch repeat and BTB domain-containing protein 4
D: REST corepressor 1
E: Kelch repeat and BTB domain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)218,8735
Polymers218,2134
Non-polymers6601
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Histone deacetylase 2 / HD2 / Protein deacylase HDAC2


Mass: 55311.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92769, histone deacetylase, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein Kelch repeat and BTB domain-containing protein 4 / BTB and kelch domain-containing protein 4


Mass: 58463.059 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
#3: Protein REST corepressor 1 / Protein CoREST


Mass: 45974.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RCOR1, KIAA0071, RCOR / Production host: Homo sapiens (human) / References: UniProt: Q9UKL0
#4: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: LHC-KBTBD4PRRmutant / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 49 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21_5207: / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 700385 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312443
ELECTRON MICROSCOPYf_angle_d0.47716871
ELECTRON MICROSCOPYf_dihedral_angle_d5.9241701
ELECTRON MICROSCOPYf_chiral_restr0.0421844
ELECTRON MICROSCOPYf_plane_restr0.0032170

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