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- EMDB-53567: An auto inhibitory loop in the MiDAC histone deacetylase complex -

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Basic information

Entry
Database: EMDB / ID: EMD-53567
TitleAn auto inhibitory loop in the MiDAC histone deacetylase complex
Map dataComposite map
Sample
  • Complex: Dimeric complex of HDAC1:MIDEAS:DNTTIP1
    • Protein or peptide: Histone deacetylase 1
    • Protein or peptide: Mitotic deacetylase-associated SANT domain protein
    • Protein or peptide: Deoxynucleotidyltransferase terminal-interacting protein 1
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: POTASSIUM ION
KeywordsHDAC1 DNTTIP1 MIDEAS histone deacetylase complex / GENE REGULATION
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
Histone deacetylase 1 / Mitotic deacetylase-associated SANT domain protein / Deoxynucleotidyltransferase terminal-interacting protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsFairall L / Schwabe JWR
Funding support United Kingdom, 1 items
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, 2025-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53567.png

Downloads & links

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Map

FileDownload / File: emd_53567.map.gz / Format: CCP4 / Size: 82 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.2 Å/pix.
x 278 pix.
= 333.878 Å		1.2 Å/pix.
x 278 pix.
= 333.878 Å		1.2 Å/pix.
x 278 pix.
= 333.878 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.201 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 8.0
Minimum - Maximum-21.305948000000001 - 54.850548000000003
Average (Standard dev.)0.0016098027 (±1.0768232)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions278278278
Spacing278278278
CellA=B=C: 333.878 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Dimeric complex of HDAC1:MIDEAS:DNTTIP1

EntireName: Dimeric complex of HDAC1:MIDEAS:DNTTIP1
Components
  • Complex: Dimeric complex of HDAC1:MIDEAS:DNTTIP1
    • Protein or peptide: Histone deacetylase 1
    • Protein or peptide: Mitotic deacetylase-associated SANT domain protein
    • Protein or peptide: Deoxynucleotidyltransferase terminal-interacting protein 1
  • Ligand: INOSITOL HEXAKISPHOSPHATE
  • Ligand: ZINC ION
  • Ligand: POTASSIUM ION

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Supramolecule #1: Dimeric complex of HDAC1:MIDEAS:DNTTIP1

SupramoleculeName: Dimeric complex of HDAC1:MIDEAS:DNTTIP1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 225 KDa

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Macromolecule #1: Histone deacetylase 1

MacromoleculeName: Histone deacetylase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / 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 #2: Mitotic deacetylase-associated SANT domain protein

MacromoleculeName: Mitotic deacetylase-associated SANT domain protein / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.268566 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TPYQSHLRSP VRLADHPSER SFELPPYTPP PILSPVREGS GLYFNAIIST STIPAPPPIT PKSAHRTLLR TNSAEVTPPV LSVMGEATP VSIEPRINVG SRFQAEIPLM RDRALAAADP HKADLVWQPW EDLESSREKQ RQVEDLLTAA CSSIFPGAGT N QELALHCL ...String:
TPYQSHLRSP VRLADHPSER SFELPPYTPP PILSPVREGS GLYFNAIIST STIPAPPPIT PKSAHRTLLR TNSAEVTPPV LSVMGEATP VSIEPRINVG SRFQAEIPLM RDRALAAADP HKADLVWQPW EDLESSREKQ RQVEDLLTAA CSSIFPGAGT N QELALHCL HESRGDILET LNKLLLKKPL RPHNHPLATY HYTGSDQWKM AERKLFNKGI AIYKKDFFLV QKLIQTKTVA QC VEFYYTY KKQVKIGRNG TLT

UniProtKB: Mitotic deacetylase-associated SANT domain protein

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Macromolecule #3: Deoxynucleotidyltransferase terminal-interacting protein 1

MacromoleculeName: Deoxynucleotidyltransferase terminal-interacting protein 1
type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.074434 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGATGDAEQP RGPSGAERGG LELGDAGAAG QLVLTNPWNI MIKHRQVQRR GRRSQMTTSF TDPAISMDLL RAVLQPSINE EIQTVFNKY MKFFQKAALN VRDNVGEEVD AEQLIQEACR SCLEQAKLLF SDGEKVIPRL THELPGIKRG RQAEEECAHR G SPLPKKRK ...String:
MGATGDAEQP RGPSGAERGG LELGDAGAAG QLVLTNPWNI MIKHRQVQRR GRRSQMTTSF TDPAISMDLL RAVLQPSINE EIQTVFNKY MKFFQKAALN VRDNVGEEVD AEQLIQEACR SCLEQAKLLF SDGEKVIPRL THELPGIKRG RQAEEECAHR G SPLPKKRK GRPPGHILSS DRAAAGMVWK PKSCEPIRRE GPKWDPARLN ESTTFVLGSR ANKALGMGGT RGRIYIKHPH LF KYAADPQ DKHWLAEQHH MRATGGKMAY LLIEEDIRDL AASDDYRGCL DLKLEELKSF VLPSWMVEKM RKYMETLRTE NEH RAVEAP PQT

UniProtKB: Deoxynucleotidyltransferase terminal-interacting protein 1

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Macromolecule #4: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #6: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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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

Concentration0.2 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHEPES
25.0 mMKClPotassium Chloride
1.0 micromolarC6H18O24P6Inositol Hexaphosphate

Details: 10 mM HEPES, 25 mM KCl, 1 micromolar Inositol Hexaphosphate
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsCrosslinked with 0.1% formaldehyde and 0.0625% glutaraldehyde

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 77.0 K / Max: 100.0 K
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 10709 / Average exposure time: 2.0 sec. / Average electron dose: 46.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3618574
CTF correctionSoftware - Name: cryoSPARC (ver. 4.4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 305895
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. 4.4.1)

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Atomic model buiding 1

Initial modelPDB ID:

6z2j


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsInitial model was built using Modelangelo and compared with PDB entry 6Z2J
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 100.7
Output model

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

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