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- PDB-8c60: Cryo-EM structure of the human SIN3B full-length complex at 3.4 A... -

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Basic information

Entry
Database: PDB / ID: 8c60
TitleCryo-EM structure of the human SIN3B full-length complex at 3.4 Angstrom resolution
Components
  • Histone deacetylase 2
  • Isoform 2 of Paired amphipathic helix protein Sin3b
  • Mortality factor 4-like protein 1
  • PHD finger protein 12
KeywordsHYDROLASE / Chromatin / Histone deacetylase / HDAC
Function / homology
Function and homology information


autosome / positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol ...autosome / positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / protein lysine delactylase activity / negative regulation of dendritic spine development / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / negative regulation of stem cell population maintenance / histone deacetylase activity, hydrolytic mechanism / ESC/E(Z) complex / histone deacetylase / regulation of stem cell differentiation / XY body / cardiac muscle hypertrophy / cellular response to dopamine / STAT3 nuclear events downstream of ALK signaling / regulation of double-strand break repair / response to caffeine / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / embryonic digit morphogenesis / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / Y chromosome / X chromosome / Sin3-type complex / NuA4 histone acetyltransferase complex / eyelid development in camera-type eye / odontogenesis of dentin-containing tooth / positive regulation of stem cell population maintenance / dendrite development / response to amyloid-beta / RNA Polymerase I Transcription Initiation / histone deacetylase complex / positive regulation of oligodendrocyte differentiation / positive regulation of proteolysis / Regulation of MECP2 expression and activity / progesterone receptor signaling pathway / hair follicle placode formation / response to hyperoxia / NF-kappaB binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to transforming growth factor beta stimulus / positive regulation of epithelial to mesenchymal transition / positive regulation of double-strand break repair via homologous recombination / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / MECP2 regulates neuronal receptors and channels / Regulation of TP53 Activity through Acetylation / cellular response to retinoic acid / heat shock protein binding / Regulation of lipid metabolism by PPARalpha / transcription repressor complex / phosphatidylinositol binding / negative regulation of cell migration / response to amphetamine / SUMOylation of chromatin organization proteins / Regulation of PTEN gene transcription / transcription corepressor binding / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription coregulator binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / response to nicotine / response to cocaine / HDACs deacetylate histones / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / circadian regulation of gene expression / negative regulation of transforming growth factor beta receptor signaling pathway / double-strand break repair via homologous recombination / Cytoprotection by HMOX1 / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / NOTCH1 Intracellular Domain Regulates Transcription / protein modification process / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / transcription corepressor activity / nucleosome / heterochromatin formation / negative regulation of neuron projection development / cellular response to heat / HATs acetylate histones / Factors involved in megakaryocyte development and platelet production / chromatin organization / fibroblast proliferation / regulation of apoptotic process / histone binding / response to lipopolysaccharide
Similarity search - Function
PHD finger protein 12, MRG binding domain / PHD finger protein 12, MRG binding domain superfamily / PHD finger protein 12 / PHD finger protein 12 MRG binding domain / Histone deacetylase interacting domain / Sin3, C-terminal / Transcriptional regulatory protein Sin3-like / Sin3 family co-repressor / C-terminal domain of Sin3a protein / Histone deacetylase (HDAC) interacting ...PHD finger protein 12, MRG binding domain / PHD finger protein 12, MRG binding domain superfamily / PHD finger protein 12 / PHD finger protein 12 MRG binding domain / Histone deacetylase interacting domain / Sin3, C-terminal / Transcriptional regulatory protein Sin3-like / Sin3 family co-repressor / C-terminal domain of Sin3a protein / Histone deacetylase (HDAC) interacting / Paired amphipathic helix / Paired amphipathic helix superfamily / Paired amphipathic helix repeat / PAH domain profile. / MRG / MRG domain / MRG, C-terminal domain superfamily / MRG / MRG domain profile. / RNA binding activity-knot of a chromodomain / RNA binding activity-knot of a chromodomain / Histone deacetylase / Histone deacetylase domain / Forkhead-associated (FHA) domain profile. / Forkhead-associated (FHA) domain / Arginase; Chain A / Chromo-like domain superfamily / : / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / SMAD/FHA domain superfamily / Ureohydrolase domain superfamily / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Paired amphipathic helix protein Sin3b / Histone deacetylase 2 / PHD finger protein 12 / Mortality factor 4-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsAlfieri, C. / Wan, S.M. / Muhammad, R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust215458/Z/19/Z United Kingdom
CitationJournal: Nat Commun / Year: 2023
Title: Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex.
Authors: Mandy S M Wan / Reyhan Muhammad / Marios G Koliopoulos / Theodoros I Roumeliotis / Jyoti S Choudhary / Claudio Alfieri /
Abstract: Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing ...Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.
History
DepositionJan 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
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Revision 1.2Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update
Revision 1.3Jul 2, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
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Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2 of Paired amphipathic helix protein Sin3b
B: Histone deacetylase 2
C: PHD finger protein 12
D: Mortality factor 4-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)336,78011
Polymers336,3724
Non-polymers4077
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 4 molecules ABCD

#1: Protein Isoform 2 of Paired amphipathic helix protein Sin3b / Histone deacetylase complex subunit Sin3b / Transcriptional corepressor Sin3b


Mass: 129547.133 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIN3B, KIAA0700 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75182
#2: Protein Histone deacetylase 2 / HD2 / Protein deacylase HDAC2


Mass: 55443.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q92769, histone deacetylase, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#3: Protein PHD finger protein 12 / PHD factor 1 / Pf1


Mass: 109841.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHF12, KIAA1523 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96QT6
#4: Protein Mortality factor 4-like protein 1 / MORF-related gene 15 protein / Protein MSL3-1 / Transcription factor-like protein MRG15


Mass: 41540.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MORF4L1, MRG15, FWP006, HSPC008, HSPC061, PP368 / Production host: Trichoplusia (butterflies/moths) / References: UniProt: Q9UBU8

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Non-polymers , 2 types, 7 molecules

#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / 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: Human SIN3B complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.385 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
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: 1600 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38352 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410627
ELECTRON MICROSCOPYf_angle_d0.74214352
ELECTRON MICROSCOPYf_dihedral_angle_d4.4991408
ELECTRON MICROSCOPYf_chiral_restr0.0461534
ELECTRON MICROSCOPYf_plane_restr0.0061862

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