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- PDB-8voj: The Cryo-EM structure of LSD1-CoREST-HDAC1 in complex with KBTBD4... -

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Entry
Database: PDB / ID: 8voj
TitleThe Cryo-EM structure of LSD1-CoREST-HDAC1 in complex with KBTBD4 enhanced by UM171 and IP6
Components
  • Histone deacetylase 1
  • Isoform 2 of Kelch repeat and BTB domain-containing protein 4
  • REST corepressor 1
KeywordsTRANSCRIPTION / molecular glue / protein degradation / E3 ligase / transcription and translation
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 / histone deacetylase activity, hydrolytic mechanism / NuRD complex / regulation of cell fate specification / negative regulation of stem cell population maintenance / endoderm development / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / protein deacetylation / histone deacetylase / regulation of stem cell differentiation / 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 / DNA methylation-dependent constitutive heterochromatin formation / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / E-box binding / Sin3-type complex / G1/S-Specific Transcription / positive regulation of stem cell population maintenance / negative regulation of intrinsic apoptotic signaling pathway / histone methyltransferase complex / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / oligodendrocyte differentiation / RNA Polymerase I Transcription Initiation / positive regulation of oligodendrocyte differentiation / histone deacetylase complex / 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 / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / RNA polymerase II core promoter sequence-specific DNA binding / heterochromatin / core promoter sequence-specific DNA binding / Nuclear events stimulated by ALK signaling in cancer / MECP2 regulates neuronal receptors and channels / cellular response to platelet-derived growth factor stimulus / Regulation of TP53 Activity through Acetylation / negative regulation of canonical NF-kappaB signal transduction / transcription repressor complex / Transcriptional and post-translational regulation of MITF-M expression and activity / Deactivation of the beta-catenin transactivating complex / SUMOylation of chromatin organization proteins / negative regulation of cell migration / Downregulation of SMAD2/3:SMAD4 transcriptional activity / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of PTEN gene transcription / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / hippocampus development / erythrocyte differentiation / transcription corepressor binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / positive regulation of smooth muscle cell proliferation / HDACs deacetylate histones / negative regulation of transforming growth factor beta receptor signaling pathway / NOTCH1 Intracellular Domain Regulates Transcription / promoter-specific chromatin binding / circadian regulation of gene expression / 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 / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / NoRC negatively regulates rRNA expression / histone deacetylase binding / neuron differentiation / transcription corepressor activity / p53 binding / heterochromatin formation / chromatin organization / Factors involved in megakaryocyte development and platelet production / 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 / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding
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 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: 3.77 Å
AuthorsXie, X. / Mao, H. / Liau, B. / Zheng, N.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
Citation
Journal: Nature / Year: 2025
Title: UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.
Authors: Megan J R Yeo / Olivia Zhang / Xiaowen Xie / Eunju Nam / N Connor Payne / Pallavi M Gosavi / Hui Si Kwok / Irtiza Iram / Ceejay Lee / Jiaming Li / Nicholas J Chen / Khanh Nguyen / Hanjie ...Authors: Megan J R Yeo / Olivia Zhang / Xiaowen Xie / Eunju Nam / N Connor Payne / Pallavi M Gosavi / Hui Si Kwok / Irtiza Iram / Ceejay Lee / Jiaming Li / Nicholas J Chen / Khanh Nguyen / Hanjie Jiang / Zhipeng A Wang / Kwangwoon Lee / Haibin Mao / Stefan A Harry / Idris A Barakat / Mariko Takahashi / Amanda L Waterbury / Marco Barone / Andrea Mattevi / Steven A Carr / Namrata D Udeshi / Liron Bar-Peled / Philip A Cole / Ralph Mazitschek / Brian B Liau / Ning Zheng /
Abstract: UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal. By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the ...UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal. By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1-CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3-neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST-HDAC1/2-KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.
#1: Journal: Protein Sci / Year: 2018
Title: UCSF ChimeraX: Meeting modern challenges in visualization and analysis.
Authors: Thomas D Goddard / Conrad C Huang / Elaine C Meng / Eric F Pettersen / Gregory S Couch / John H Morris / Thomas E Ferrin /
Abstract: UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and ...UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high-quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux.
History
DepositionJan 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 18, 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: Isoform 2 of Kelch repeat and BTB domain-containing protein 4
B: Isoform 2 of 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)222,2767
Polymers221,0974
Non-polymers1,1793
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

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Protein , 3 types, 4 molecules ABCD

#1: Protein Isoform 2 of Kelch repeat and BTB domain-containing protein 4 / BTB and kelch domain-containing protein 4


Mass: 59971.711 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: Homo sapiens (human)
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: Homo sapiens (human) / References: UniProt: Q9UKL0

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Non-polymers , 3 types, 3 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Zn / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#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
#6: Chemical ChemComp-A1ACV / (1r,4r)-N~1~-[(7P)-2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl]cyclohexane-1,4-diamine


Mass: 453.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N9 / Feature type: SUBJECT OF INVESTIGATION

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Details

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-K4 / 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: 54.4 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: 3.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 186315 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312390
ELECTRON MICROSCOPYf_angle_d0.63816797
ELECTRON MICROSCOPYf_dihedral_angle_d5.6071700
ELECTRON MICROSCOPYf_chiral_restr0.0451829
ELECTRON MICROSCOPYf_plane_restr0.0042167

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