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Yorodumi- PDB-6nts: Protein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in com... -
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-Basic information
Entry | Database: PDB / ID: 6nts | |||||||||
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Title | Protein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP) | |||||||||
Components |
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Keywords | HYDROLASE/ACTIVATOR / Holoenzyme complex / Phosphatase / Activator / HYDROLASE-ACTIVATOR complex | |||||||||
Function / homology | Function and homology information negative regulation of lipid kinase activity / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / protein serine/threonine phosphatase complex / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / protein phosphatase type 2A complex ...negative regulation of lipid kinase activity / meiotic spindle elongation / Integration of energy metabolism / PP2A-mediated dephosphorylation of key metabolic factors / regulation of microtubule binding / protein serine/threonine phosphatase complex / mitotic sister chromatid separation / MASTL Facilitates Mitotic Progression / regulation of meiotic cell cycle process involved in oocyte maturation / protein phosphatase type 2A complex / meiotic sister chromatid cohesion, centromeric / peptidyl-serine dephosphorylation / peptidyl-threonine dephosphorylation / FAR/SIN/STRIPAK complex / positive regulation of microtubule binding / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / female meiotic nuclear division / protein phosphatase regulator activity / protein antigen binding / GABA receptor binding / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Initiation of Nuclear Envelope (NE) Reformation / ERKs are inactivated / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / negative regulation of epithelial to mesenchymal transition / M band / regulation of growth / negative regulation of protein localization to plasma membrane / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of glycolytic process through fructose-6-phosphate / positive regulation of NLRP3 inflammasome complex assembly / myosin phosphatase activity / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / Platelet sensitization by LDL / protein-serine/threonine phosphatase / Cyclin A/B1/B2 associated events during G2/M transition / regulation of cell differentiation / negative regulation of hippo signaling / ERK/MAPK targets / protein phosphatase activator activity / T cell homeostasis / regulation of G1/S transition of mitotic cell cycle / mesoderm development / phosphoprotein phosphatase activity / chromosome, centromeric region / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / DARPP-32 events / lateral plasma membrane / meiotic cell cycle / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / : / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / Resolution of Sister Chromatid Cohesion / protein dephosphorylation / AURKA Activation by TPX2 / protein tyrosine phosphatase activity / chromosome segregation / RHO GTPases Activate Formins / kinase binding / response to lead ion / RAF activation / regulation of protein phosphorylation / Spry regulation of FGF signaling / Degradation of beta-catenin by the destruction complex / tau protein binding / positive regulation of protein serine/threonine kinase activity / PKR-mediated signaling / Cyclin D associated events in G1 / spindle pole / Z disc / Regulation of TP53 Degradation / Negative regulation of MAPK pathway / Separation of Sister Chromatids / microtubule cytoskeleton / Regulation of PLK1 Activity at G2/M Transition / mitotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein-containing complex assembly / intracellular signal transduction / neuron projection / membrane raft / protein heterodimerization activity / centrosome Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.63 Å | |||||||||
Authors | Huang, W. / Taylor, D. | |||||||||
Funding support | United States, 1items
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Citation | Journal: Cell / Year: 2020 Title: Selective PP2A Enhancement through Biased Heterotrimer Stabilization. Authors: Daniel Leonard / Wei Huang / Sudeh Izadmehr / Caitlin M O'Connor / Danica D Wiredja / Zhizhi Wang / Nilesh Zaware / Yinghua Chen / Daniela M Schlatzer / Janna Kiselar / Nikhil Vasireddi / ...Authors: Daniel Leonard / Wei Huang / Sudeh Izadmehr / Caitlin M O'Connor / Danica D Wiredja / Zhizhi Wang / Nilesh Zaware / Yinghua Chen / Daniela M Schlatzer / Janna Kiselar / Nikhil Vasireddi / Stefan Schüchner / Abbey L Perl / Matthew D Galsky / Wenqing Xu / David L Brautigan / Egon Ogris / Derek J Taylor / Goutham Narla / Abstract: Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to ...Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets. | |||||||||
History |
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-Structure visualization
Movie |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6nts.cif.gz | 232.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6nts.ent.gz | 181.9 KB | Display | PDB format |
PDBx/mmJSON format | 6nts.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6nts_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 6nts_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 6nts_validation.xml.gz | 49.2 KB | Display | |
Data in CIF | 6nts_validation.cif.gz | 73.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/nt/6nts ftp://data.pdbj.org/pub/pdb/validation_reports/nt/6nts | HTTPS FTP |
-Related structure data
Related structure data | 0510MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 65378.344 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R1A / Production host: Escherichia coli (E. coli) / References: UniProt: P30153 | ||
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#2: Protein | Mass: 56266.555 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R5A / Production host: Escherichia coli (E. coli) / References: UniProt: Q15172 | ||
#3: Protein | Mass: 35021.500 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2CA / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P67775, protein-serine/threonine phosphatase | ||
#4: Chemical | ChemComp-L2J / | ||
#5: Chemical | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: PP2A Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP) Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.02 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 40 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.18rc3_3805: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 83784 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 139.2 Å2 | ||||||||||||||||||||||||
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