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- PDB-8vrt: The structure of LSD1-CoREST-HDAC1 in complex with KBTBD4R313PRR ... -

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Basic information

Entry
Database: PDB / ID: 8vrt
TitleThe structure of LSD1-CoREST-HDAC1 in complex with KBTBD4R313PRR mutant
Components
  • Histone deacetylase 1
  • 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


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 / fungiform papilla formation / epidermal cell differentiation / eyelid development in camera-type eye / positive regulation of megakaryocyte differentiation ...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 / fungiform papilla formation / epidermal cell differentiation / eyelid development in camera-type eye / positive regulation of megakaryocyte differentiation / histone decrotonylase activity / negative regulation of androgen receptor signaling pathway / NuRD complex / DNA repair complex / regulation of cell fate specification / negative regulation of stem cell population maintenance / regulation of stem cell differentiation / histone deacetylase activity, hydrolytic mechanism / histone deacetylase / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / positive regulation of intracellular estrogen receptor signaling pathway / odontogenesis of dentin-containing tooth / STAT3 nuclear events downstream of ALK signaling / Regulation of MITF-M-dependent genes involved in apoptosis / Transcription of E2F targets under negative control by DREAM complex / embryonic digit morphogenesis / DNA methylation-dependent constitutive heterochromatin formation / histone deacetylase activity / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / Sin3-type complex / G1/S-Specific Transcription / positive regulation of stem cell population maintenance / transcription repressor complex / histone deacetylase complex / E-box binding / histone methyltransferase complex / RNA Polymerase I Transcription Initiation / G0 and Early G1 / hair follicle placode formation / host-mediated suppression of viral transcription / cellular response to platelet-derived growth factor stimulus / Regulation of MECP2 expression and activity / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / NF-kappaB binding / 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 / Regulation of TP53 Activity through Acetylation / MECP2 regulates neuronal receptors and channels / heterochromatin / Nuclear events stimulated by ALK signaling in cancer / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of smooth muscle cell proliferation / negative regulation of cell migration / regulation of embryonic development / erythrocyte differentiation / negative regulation of transforming growth factor beta receptor signaling pathway / transcription corepressor binding / Regulation of PTEN gene transcription / SUMOylation of chromatin organization proteins / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / circadian regulation of gene expression / Regulation of endogenous retroelements by KRAB-ZFP proteins / HDACs deacetylate histones / negative regulation of canonical Wnt signaling pathway / promoter-specific chromatin binding / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / Downregulation of SMAD2/3:SMAD4 transcriptional activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Deactivation of the beta-catenin transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Negative Regulation of CDH1 Gene Transcription / NoRC negatively regulates rRNA expression / Formation of the beta-catenin:TCF transactivating complex / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / p53 binding / transcription corepressor activity / transcription regulator complex / Factors involved in megakaryocyte development and platelet production / heterochromatin formation / chromatin organization / DNA-binding transcription factor binding / Estrogen-dependent gene expression / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromatin remodeling / ribonucleoprotein complex / negative regulation of gene expression / negative regulation of DNA-templated transcription / neuronal cell body / positive regulation of gene expression
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 / Histone deacetylase family / Kelch-type beta propeller / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Myb-like DNA-binding 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 1 / 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: 3.42 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
DepositionJan 22, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)218,8056
Polymers218,0794
Non-polymers7252
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 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
#2: Protein Histone deacetylase 1 / HD1 / Protein deacetylase HDAC1 / Protein decrotonylase HDAC1


Mass: 55178.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC1, RPD3L1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q13547, histone deacetylase, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#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: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UKL0
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: 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
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

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: 49 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286: / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 110048 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312526
ELECTRON MICROSCOPYf_angle_d0.52716985
ELECTRON MICROSCOPYf_dihedral_angle_d4.2731685
ELECTRON MICROSCOPYf_chiral_restr0.0431852
ELECTRON MICROSCOPYf_plane_restr0.0042183

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