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- EMDB-53565: Focussed map (bottom) MiDAC complex -

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Basic information

Entry
Database: EMDB / ID: EMD-53565
TitleFocussed map (bottom) MiDAC complex
Map dataFocussed map
Sample
  • Complex: Dimeric complex of HDAC1:MIDEAS:DNTTIP1
KeywordsHDAC1 DNTTIP1 MIDEAS histone deacetylase complex / GENE REGULATION
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.89 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) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateMar 18, 2026-
Current statusMar 18, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53565.png

Downloads & links

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Map

FileDownload / File: emd_53565.map.gz / Format: CCP4 / Size: 82 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocussed map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (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: 0.2
Minimum - Maximum-2.3062193 - 4.5215592
Average (Standard dev.)0.00004686654 (±0.02305519)
SymmetrySpace group: 1
Details

EMDB XML:

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

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Supplemental data

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Half map: #1

Fileemd_53565_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_53565_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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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

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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-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 225 KDa

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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: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 305895
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. 4.4.1)
FSC plot (resolution estimation)

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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

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