+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-0510 | |||||||||
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タイトル | Protein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP) | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Holoenzyme complex / Phosphatase / Activator / HYDROLASE-ACTIVATOR complex | |||||||||
機能・相同性 | 機能・相同性情報 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 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.63 Å | |||||||||
データ登録者 | Huang W / Taylor D | |||||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Cell / 年: 2020 タイトル: Selective PP2A Enhancement through Biased Heterotrimer Stabilization. 著者: 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 / ...著者: 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 / 要旨: 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. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_0510.map.gz | 69.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-0510-v30.xml emd-0510.xml | 18.1 KB 18.1 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_0510_fsc.xml | 12 KB | 表示 | FSCデータファイル |
画像 | emd_0510.png | 255.7 KB | ||
マスクデータ | emd_0510_msk_1.map | 144.7 MB | マスクマップ | |
Filedesc metadata | emd-0510.cif.gz | 6.6 KB | ||
その他 | emd_0510_half_map_1.map.gz emd_0510_half_map_2.map.gz | 132.3 MB 134.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-0510 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0510 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_0510_validation.pdf.gz | 1 MB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_0510_full_validation.pdf.gz | 1 MB | 表示 | |
XML形式データ | emd_0510_validation.xml.gz | 19.3 KB | 表示 | |
CIF形式データ | emd_0510_validation.cif.gz | 25.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0510 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0510 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_0510.map.gz / 形式: CCP4 / 大きさ: 144.7 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.064 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
ファイル | emd_0510_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_0510_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_0510_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : PP2A Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Mo...
全体 | 名称: PP2A Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP) |
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要素 |
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-超分子 #1: PP2A Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Mo...
超分子 | 名称: PP2A Aalpha-B56alpha-Calpha holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP) タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit...
分子 | 名称: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 65.378344 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: MAAADGDDSL YPIAVLIDEL RNEDVQLRLN SIKKLSTIAL ALGVERTRSE LLPFLTDTIY DEDEVLLALA EQLGTFTTLV GGPEYVHCL LPPLESLATV EETVVRDKAV ESLRAISHEH SPSDLEAHFV PLVKRLAGGD WFTSRTSACG LFSVCYPRVS S AVKAELRQ ...文字列: MAAADGDDSL YPIAVLIDEL RNEDVQLRLN SIKKLSTIAL ALGVERTRSE LLPFLTDTIY DEDEVLLALA EQLGTFTTLV GGPEYVHCL LPPLESLATV EETVVRDKAV ESLRAISHEH SPSDLEAHFV PLVKRLAGGD WFTSRTSACG LFSVCYPRVS S AVKAELRQ YFRNLCSDDT PMVRRAAASK LGEFAKVLEL DNVKSEIIPM FSNLASDEQD SVRLLAVEAC VNIAQLLPQE DL EALVMPT LRQAAEDKSW RVRYMVADKF TELQKAVGPE ITKTDLVPAF QNLMKDCEAE VRAAASHKVK EFCENLSADC REN VIMSQI LPCIKELVSD ANQHVKSALA SVIMGLSPIL GKDNTIEHLL PLFLAQLKDE CPEVRLNIIS NLDCVNEVIG IRQL SQSLL PAIVELAEDA KWRVRLAIIE YMPLLAGQLG VEFFDEKLNS LCMAWLVDHV YAIREAATSN LKKLVEKFGK EWAHA TIIP KVLAMSGDPN YLHRMTTLFC INVLSEVCGQ DITTKHMLPT VLRMAGDPVA NVRFNVAKSL QKIGPILDNS TLQSEV KPI LEKLTQDQDV DVKYFAQEAL TVLSLA UniProtKB: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform |
-分子 #2: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit...
分子 | 名称: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 56.266555 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: MSSSSPPAGA ASAAISASEK VDGFTRKSVR KAQRQKRSQG SSQFRSQGSQ AELHPLPQLK DATSNEQQEL FCQKLQQCCI LFDFMDSVS DLKSKEIKRA TLNELVEYVS TNRGVIVESA YSDIVKMISA NIFRTLPPSD NPDFDPEEDE PTLEASWPHI Q LVYEFFLR ...文字列: MSSSSPPAGA ASAAISASEK VDGFTRKSVR KAQRQKRSQG SSQFRSQGSQ AELHPLPQLK DATSNEQQEL FCQKLQQCCI LFDFMDSVS DLKSKEIKRA TLNELVEYVS TNRGVIVESA YSDIVKMISA NIFRTLPPSD NPDFDPEEDE PTLEASWPHI Q LVYEFFLR FLESPDFQPS IAKRYIDQKF VQQLLELFDS EDPRERDFLK TVLHRIYGKF LGLRAFIRKQ INNIFLRFIY ET EHFNGVA ELLEILGSII NGFALPLKAE HKQFLMKVLI PMHTAKGLAL FHAQLAYCVV QFLEKDTTLT EPVIRGLLKF WPK TCSQKE VMFLGEIEEI LDVIEPTQFK KIEEPLFKQI SKCVSSSHFQ VAERALYFWN NEYILSLIEE NIDKILPIMF ASLY KISKE HWNPTIVALV YNVLKTLMEM NGKLFDDLTS SYKAERQREK KKELEREELW KKLEELKLKK ALEKQNSAYN MHSIL SNTS AE UniProtKB: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform |
-分子 #3: Serine/threonine-protein phosphatase 2A catalytic subunit alpha i...
分子 | 名称: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO / EC番号: protein-serine/threonine phosphatase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 35.0215 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG QFHDLMELFR IGGKSPDTNY LFMGDYVNR GYYSVETVTL LVALKVRYRE RITILRGNHE SRQITQVYGF YDECLRKYGN ANVWKYFTDL FDYLPLTALV D GQIFCLHG ...文字列: MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG QFHDLMELFR IGGKSPDTNY LFMGDYVNR GYYSVETVTL LVALKVRYRE RITILRGNHE SRQITQVYGF YDECLRKYGN ANVWKYFTDL FDYLPLTALV D GQIFCLHG GLSPSIDTLD HIRALDRLQE VPHEGPMCDL LWSDPDDRGG WGISPRGAGY TFGQDISETF NHANGLTLVS RA HQLVMEG YNWCHDRNVV TIFSAPNYCY RCGNQAAIME LDDTLKYSFL QFDPAPRRGE PHVTYF(MLL) UniProtKB: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform |
-分子 #4: N-[(1R,2R,3S)-2-hydroxy-3-(10H-phenoxazin-10-yl)cyclohexyl]-4-(tr...
分子 | 名称: N-[(1R,2R,3S)-2-hydroxy-3-(10H-phenoxazin-10-yl)cyclohexyl]-4-(trifluoromethoxy)benzene-1-sulfonamide タイプ: ligand / ID: 4 / コピー数: 1 / 式: L2J |
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分子量 | 理論値: 520.521 Da |
Chemical component information | ChemComp-L2J: |
-分子 #5: MANGANESE (II) ION
分子 | 名称: MANGANESE (II) ION / タイプ: ligand / ID: 5 / コピー数: 2 / 式: MN |
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分子量 | 理論値: 54.938 Da |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.02 |
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グリッド | 詳細: unspecified |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 平均電子線量: 40.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: SPOT SCAN / 撮影モード: BRIGHT FIELD |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |