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

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Basic information

Entry
Database: PDB / ID: 8bpc
TitleCryo-EM structure of the human SIN3B histone deacetylase core complex with SAHA 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 / protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol ...autosome / protein de-2-hydroxyisobutyrylase activity / positive regulation of male mating behavior / negative regulation of peptidyl-lysine acetylation / p75NTR negatively regulates cell cycle via SC1 / epidermal cell differentiation / negative regulation of dendritic spine development / histone decrotonylase activity / fungiform papilla formation / behavioral response to ethanol / negative regulation of MHC class II biosynthetic process / NuRD complex / positive regulation of interleukin-1 production / regulation of cell fate specification / XY body / negative regulation of stem cell population maintenance / EGR2 and SOX10-mediated initiation of Schwann cell myelination / negative regulation of transcription by competitive promoter binding / ESC/E(Z) complex / regulation of stem cell differentiation / STAT3 nuclear events downstream of ALK signaling / cellular response to dopamine / histone deacetylase / cardiac muscle hypertrophy / protein lysine deacetylase activity / positive regulation of signaling receptor activity / response to caffeine / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / histone deacetylase activity / embryonic digit morphogenesis / positive regulation of oligodendrocyte differentiation / positive regulation of stem cell population maintenance / Sin3-type complex / Notch-HLH transcription pathway / Y chromosome / dendrite development / eyelid development in camera-type eye / X chromosome / odontogenesis of dentin-containing tooth / positive regulation of proteolysis / RNA Polymerase I Transcription Initiation / response to amyloid-beta / histone deacetylase complex / hair follicle placode formation / Regulation of MECP2 expression and activity / NF-kappaB binding / positive regulation of collagen biosynthetic process / response to hyperoxia / positive regulation of epithelial to mesenchymal transition / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / heterochromatin formation / MECP2 regulates neuronal receptors and channels / cellular response to retinoic acid / positive regulation of tyrosine phosphorylation of STAT protein / Regulation of TP53 Activity through Acetylation / cellular response to transforming growth factor beta stimulus / response to amphetamine / heat shock protein binding / transcription repressor complex / Regulation of lipid metabolism by PPARalpha / SUMOylation of chromatin organization proteins / phosphatidylinositol binding / negative regulation of cell migration / transcription corepressor binding / response to cocaine / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / response to nicotine / Regulation of PTEN gene transcription / promoter-specific chromatin binding / HDACs deacetylate histones / negative regulation of transforming growth factor beta receptor signaling pathway / circadian regulation of gene expression / protein modification process / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / negative regulation of DNA-binding transcription factor activity / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / transcription corepressor activity / positive regulation of tumor necrosis factor production / negative regulation of neuron projection development / cellular response to heat / Factors involved in megakaryocyte development and platelet production / histone binding / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / response to lipopolysaccharide / chromosome, telomeric region / chromatin remodeling / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of cell population proliferation / chromatin / negative regulation of apoptotic process / positive regulation of DNA-templated transcription
Similarity search - Function
PHD finger protein 12, MRG binding domain / PHD finger protein 12, MRG binding domain superfamily / 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 ...PHD finger protein 12, MRG binding domain / PHD finger protein 12, MRG binding domain superfamily / 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
OCTANEDIOIC ACID HYDROXYAMIDE PHENYLAMIDE / 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 1.1May 17, 2023Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _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)226,7889
Polymers226,2473
Non-polymers5416
Water79344
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, 50 molecules

#4: Chemical ChemComp-SHH / OCTANEDIOIC ACID HYDROXYAMIDE PHENYLAMIDE / SAHA


Mass: 264.320 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / 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
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 44 / 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 FIELDBright-field microscopy / 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: 28673 / Symmetry type: POINT

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