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- PDB-8bpb: Cryo-EM structure of the human SIN3B histone deacetylase core com... -

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Basic information

Entry
Database: PDB / ID: 8bpb
TitleCryo-EM structure of the human SIN3B histone deacetylase core complex at 2.8 Angstrom
Components
  • Histone deacetylase 2
  • Isoform 2 of Paired amphipathic helix protein Sin3b
  • PHD finger protein 12
KeywordsGENE REGULATION / HDAC / Chromatin / Cell cycle / transcription
Function / homology
Function and homology information


autosome / positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / : / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / fungiform papilla formation / epidermal cell differentiation / eyelid development in camera-type eye / negative regulation of dendritic spine development ...autosome / positive regulation of male mating behavior / protein de-2-hydroxyisobutyrylase activity / : / protein lysine delactylase activity / p75NTR negatively regulates cell cycle via SC1 / fungiform papilla formation / epidermal cell differentiation / eyelid development in camera-type eye / negative regulation of dendritic spine development / histone decrotonylase activity / negative regulation of transcription initiation by RNA polymerase II / 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 stem cell population maintenance / regulation of stem cell differentiation / histone deacetylase activity, hydrolytic mechanism / histone deacetylase / XY body / ESC/E(Z) complex / positive regulation of intracellular estrogen receptor signaling pathway / cardiac muscle hypertrophy / behavioral response to ethanol / odontogenesis of dentin-containing tooth / cellular response to dopamine / STAT3 nuclear events downstream of ALK signaling / embryonic digit morphogenesis / histone deacetylase activity / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / response to caffeine / Notch-HLH transcription pathway / Y chromosome / positive regulation of oligodendrocyte differentiation / X chromosome / histone deacetylase complex / positive regulation of stem cell population maintenance / dendrite development / Sin3-type complex / response to amyloid-beta / positive regulation of proteolysis / progesterone receptor signaling pathway / RNA Polymerase I Transcription Initiation / response to hyperoxia / hair follicle placode formation / cellular response to transforming growth factor beta stimulus / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Regulation of MECP2 expression and activity / positive regulation of epithelial to mesenchymal transition / NF-kappaB binding / Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 / cellular response to retinoic acid / Regulation of TP53 Activity through Acetylation / MECP2 regulates neuronal receptors and channels / Regulation of lipid metabolism by PPARalpha / heat shock protein binding / transcription repressor complex / response to amphetamine / negative regulation of cell migration / regulation of embryonic development / phosphatidylinositol binding / negative regulation of transforming growth factor beta receptor signaling pathway / Regulation of PTEN gene transcription / transcription corepressor binding / transcription coregulator binding / SUMOylation of chromatin organization proteins / response to cocaine / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / response to nicotine / circadian regulation of gene expression / Regulation of endogenous retroelements by KRAB-ZFP proteins / negative regulation of neuron projection development / HDACs deacetylate histones / Cytoprotection by HMOX1 / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / promoter-specific chromatin binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Negative Regulation of CDH1 Gene Transcription / 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 / cellular response to hydrogen peroxide / positive regulation of tumor necrosis factor production / transcription corepressor activity / cellular response to heat / histone binding / Factors involved in megakaryocyte development and platelet production / response to lipopolysaccharide / heterochromatin formation / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding
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. / Histone deacetylase / Forkhead-associated (FHA) domain profile. / Forkhead-associated (FHA) domain / 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
Similarity search - Domain/homology
ACETATE ION / Paired amphipathic helix protein Sin3b / Histone deacetylase 2 / PHD finger protein 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWan, M.S.M. / Muhammad, R. / Koliopolous, M.G. / Alfieri, C.
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
DepositionNov 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,5839
Polymers226,2473
Non-polymers3356
Water21612
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules ABC

#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: 41257.059 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

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Non-polymers , 4 types, 18 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: SIN3B core complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.15 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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 500 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 41979 / Symmetry type: POINT

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