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- PDB-9r4i: An auto inhibitory loop in the MiDAC histone deacetylase complex -

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Basic information

Entry
Database: PDB / ID: 9r4i
TitleAn auto inhibitory loop in the MiDAC histone deacetylase complex
Components
  • Deoxynucleotidyltransferase terminal-interacting protein 1
  • Histone deacetylase 1
  • Mitotic deacetylase-associated SANT domain protein
KeywordsGENE REGULATION / HDAC1 DNTTIP1 MIDEAS histone deacetylase complex
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 / histone decrotonylase activity / fungiform papilla formation / NuRD complex ...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 / histone decrotonylase activity / fungiform papilla formation / NuRD complex / regulation of cell fate specification / negative regulation of androgen receptor signaling pathway / 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 / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / histone deacetylase activity / embryonic digit morphogenesis / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression, epigenetic / G1/S-Specific Transcription / negative regulation of intrinsic apoptotic signaling pathway / histone deacetylase complex / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / Sin3-type complex / positive regulation of stem cell population maintenance / E-box binding / oligodendrocyte differentiation / positive regulation of oligodendrocyte differentiation / RNA Polymerase I Transcription Initiation / G0 and Early G1 / host-mediated suppression of viral transcription / Regulation of MECP2 expression and activity / hair follicle placode formation / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / core promoter sequence-specific DNA binding / RNA polymerase II core promoter sequence-specific DNA binding / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / nucleosome binding / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / heterochromatin / cellular response to platelet-derived growth factor stimulus / Nuclear events stimulated by ALK signaling in cancer / transcription repressor complex / positive regulation of smooth muscle cell proliferation / Transcriptional and post-translational regulation of MITF-M expression and activity / negative regulation of cell migration / negative regulation of canonical NF-kappaB signal transduction / SUMOylation of chromatin organization proteins / Regulation of PTEN gene transcription / transcription corepressor binding / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Regulation of endogenous retroelements by KRAB-ZFP proteins / hippocampus development / circadian regulation of gene expression / HDACs deacetylate histones / promoter-specific chromatin binding / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / negative regulation of transforming growth factor beta receptor signaling pathway / Deactivation of the beta-catenin transactivating complex / Downregulation of SMAD2/3:SMAD4 transcriptional activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / 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 / chromosome / Factors involved in megakaryocyte development and platelet production / chromatin organization / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor binding / 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 / negative regulation of gene expression / negative regulation of DNA-templated transcription
Similarity search - Function
Terminal deoxynucleotidyltransferase-interacting factor 1 / DNTTIP1, dimerisation domain / : / DNTTIP1 dimerisation domain / TdIF1, C-terminal / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 ...Terminal deoxynucleotidyltransferase-interacting factor 1 / DNTTIP1, dimerisation domain / : / DNTTIP1 dimerisation domain / TdIF1, C-terminal / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone deacetylase / : / SANT domain profile. / SANT domain / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Homeobox-like domain superfamily
Similarity search - Domain/homology
INOSITOL HEXAKISPHOSPHATE / : / Histone deacetylase 1 / Mitotic deacetylase-associated SANT domain protein / Deoxynucleotidyltransferase terminal-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsFairall, L. / Schwabe, J.W.R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust222493/Z/21/Z United Kingdom
CitationJournal: Nat Commun / Year: 2025
Title: A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome.
Authors: Louise Fairall / Kristupas Sirvydis / Robert E Turnbull / Suzan Jg Knottnerus / Oksana Gonchar / Frederick W Muskett / Rebekah Jukes-Jones / Lonneke van Brussel / Ellen van de Geer / Koen ...Authors: Louise Fairall / Kristupas Sirvydis / Robert E Turnbull / Suzan Jg Knottnerus / Oksana Gonchar / Frederick W Muskett / Rebekah Jukes-Jones / Lonneke van Brussel / Ellen van de Geer / Koen van Gassen / Paul Badenhorst / Diana Johnson / Paulien A Terhal / Peter M van Hasselt / Richard H van Jaarsveld / John Wr Schwabe /
Abstract: MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. ...MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. Here, we report two unrelated individuals, with a multisystem disorder characterised by delayed speech development, joint contractures, dysmorphic features and dysmotility of the gut. Both individuals have the same de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser). A cryoEM structure of the MiDAC complex reveals that this amino acid is located in a conserved auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest that the variant results in loop displacement leading to elevated deacetylase activity. In support, we observe reciprocal gene expression changes in patient fibroblasts compared with a cell line following rapid MiDAC degradation. Our results establish MIDEAS as a dominant monogenic disease gene and that hyperactivity of the MiDAC complex results in a characteristic multisystem disorder.
History
DepositionMay 7, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone deacetylase 1
B: Mitotic deacetylase-associated SANT domain protein
C: Deoxynucleotidyltransferase terminal-interacting protein 1
D: Histone deacetylase 1
E: Mitotic deacetylase-associated SANT domain protein
F: Deoxynucleotidyltransferase terminal-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)244,65114
Polymers243,0446
Non-polymers1,6078
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, 6 molecules ADBECF

#1: Protein Histone deacetylase 1 / HD1


Mass: 55178.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC1, RPD3L1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q13547, histone deacetylase
#2: Protein Mitotic deacetylase-associated SANT domain protein / ELM2 and SANT domain-containing protein 1


Mass: 29268.566 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MIDEAS, C14orf117, C14orf43, ELMSAN1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q6PJG2
#3: Protein Deoxynucleotidyltransferase terminal-interacting protein 1 / Terminal deoxynucleotidyltransferase-interacting factor 1 / TdIF1 / TdT-interacting factor 1


Mass: 37074.434 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNTTIP1, C20orf167, TDIF1 / Plasmid: pcDNA3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q9H147

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Non-polymers , 3 types, 8 molecules

#4: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H18O24P6 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K

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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: Dimeric complex of HDAC1:MIDEAS:DNTTIP1 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.225 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F / Plasmid: pcDNA3
Buffer solutionpH: 7.5
Details: 10 mM HEPES, 25 mM KCl, 1 micromolar Inositol Hexaphosphate
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMHEPESC8H18N2O4S1
225 mMPotassium ChlorideKCl1
31 micromolarInositol HexaphosphateC6H18O24P61
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Crosslinked with 0.1% formaldehyde and 0.0625% glutaraldehyde
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 77 K
Image recordingAverage exposure time: 2 sec. / Electron dose: 46.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 10709
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
2EPUimage acquisition
4cryoSPARC4.4.1CTF correction
7Coot0.9.6model fitting
9PHENIX1.21.1_5286model refinement
11cryoSPARC4.4.1final Euler assignment
12cryoSPARC4.4.1classification
13cryoSPARC4.4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3618574
3D reconstructionResolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 305895 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 100.7 / Protocol: AB INITIO MODEL / Space: REAL
Details: Initial model was built using Modelangelo and compared with PDB entry 6Z2J
Atomic model buildingPDB-ID: 6Z2J

6z2j


Accession code: 6Z2J / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.92 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310722
ELECTRON MICROSCOPYf_angle_d0.47514506
ELECTRON MICROSCOPYf_dihedral_angle_d5.5581499
ELECTRON MICROSCOPYf_chiral_restr0.0371532
ELECTRON MICROSCOPYf_plane_restr0.0041865

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