+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-29941 | |||||||||
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タイトル | HPV16 E6-E6AP-p53 complex | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Complex / HPV / ubiquitin ligase (ユビキチンリガーゼ) / tumor suppressor (がん抑制遺伝子) / VIRAL PROTEIN (ウイルスタンパク質) | |||||||||
機能・相同性 | 機能・相同性情報 sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / motor learning / negative regulation of dendritic spine morphogenesis / regulation of ubiquitin-dependent protein catabolic process / prostate gland growth / HECT-type E3 ubiquitin transferase / regulation of proteolysis / activation of GTPase activity ...sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / motor learning / negative regulation of dendritic spine morphogenesis / regulation of ubiquitin-dependent protein catabolic process / prostate gland growth / HECT-type E3 ubiquitin transferase / regulation of proteolysis / activation of GTPase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / 転写 (生物学) / bone marrow development / circadian behavior / histone deacetylase regulator activity / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / germ cell nucleus / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / T cell lineage commitment / positive regulation of execution phase of apoptosis / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / positive regulation of cardiac muscle cell apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / T cell proliferation involved in immune response / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / maltose binding / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / androgen receptor signaling pathway / locomotory exploration behavior / maltose transport / Zygotic genome activation (ZGA) / maltodextrin transmembrane transport / necroptotic process / progesterone receptor signaling pathway / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / マイトファジー / SUMOylation of transcription factors / negative regulation of telomere maintenance via telomerase / general transcription initiation factor binding / intrinsic apoptotic signaling pathway by p53 class mediator / carbohydrate transmembrane transporter activity / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / ヘイフリック限界 / chromosome organization / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to UV-C / : / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / glial cell proliferation / embryonic organ development / positive regulation of RNA polymerase II transcription preinitiation complex assembly / protein autoubiquitination / Pyroptosis 類似検索 - 分子機能 | |||||||||
生物種 | Escherichia coli (大腸菌) / Homo sapiens (ヒト) / Human papillomavirus type 16 (パピローマウイルス) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.38 Å | |||||||||
データ登録者 | Bratkowski MA / Wang JCK / Hao Q / Nile AH | |||||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Nat Commun / 年: 2024 タイトル: Structure of the p53 degradation complex from HPV16. 著者: John C K Wang / Hannah T Baddock / Amirhossein Mafi / Ian T Foe / Matthew Bratkowski / Ting-Yu Lin / Zena D Jensvold / Magdalena Preciado López / David Stokoe / Dan Eaton / Qi Hao / Aaron H Nile / 要旨: Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3- ...Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_29941.map.gz | 230.2 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-29941-v30.xml emd-29941.xml | 21.8 KB 21.8 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_29941_fsc.xml | 14.2 KB | 表示 | FSCデータファイル |
画像 | emd_29941.png | 43.6 KB | ||
マスクデータ | emd_29941_msk_1.map | 244.1 MB | マスクマップ | |
Filedesc metadata | emd-29941.cif.gz | 7.4 KB | ||
その他 | emd_29941_half_map_1.map.gz emd_29941_half_map_2.map.gz | 226.8 MB 226.8 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-29941 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29941 | HTTPS FTP |
-関連構造データ
関連構造データ | 8gcrMC M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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_29941.map.gz / 形式: CCP4 / 大きさ: 244.1 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: 0.83 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-マスク #1
ファイル | emd_29941_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: #2
ファイル | emd_29941_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: #1
ファイル | emd_29941_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 : Ternary complex of HPV16 E6, E6AP, and p53
全体 | 名称: Ternary complex of HPV16 E6, E6AP, and p53 |
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要素 |
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-超分子 #1: Ternary complex of HPV16 E6, E6AP, and p53
超分子 | 名称: Ternary complex of HPV16 E6, E6AP, and p53 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 |
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-超分子 #2: HPV16 E6 - MBP Fusion
超分子 | 名称: HPV16 E6 - MBP Fusion / タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #1 |
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由来(天然) | 生物種: Escherichia coli (大腸菌) |
-超分子 #3: p53
超分子 | 名称: p53 / タイプ: complex / ID: 3 / 親要素: 1 / 含まれる分子: #2 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-超分子 #4: E6AP
超分子 | 名称: E6AP / タイプ: complex / ID: 4 / 親要素: 1 / 含まれる分子: #3 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Maltose/maltodextrin-binding periplasmic protein,Protein E6
分子 | 名称: Maltose/maltodextrin-binding periplasmic protein,Protein E6 タイプ: protein_or_peptide / ID: 1 詳細: The cysteine to serine mutations are in the protein E6 portion of the chimeric construct.,The cysteine to serine mutations are in the protein E6 portion of the chimeric construct. コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Human papillomavirus type 16 (パピローマウイルス) |
分子量 | 理論値: 61.190582 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY ...文字列: MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFGG YAQSGLLAEI TPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE LKAKGKSALM FNLQEPYFTW P LIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NKGETAMTIN GPWAWSNIDT SK VNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPLGAVALKS YEEELAKDPR IAA TMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TRITKGGGGS ENLYFQGMHQ KRTAMFQDPQ ERPR KLPQL CTELQTTIHD IILECVYCKQ QLLRREVYDF AFRDLCIVYR DGNPYAVCDK CLKFYSKISE YRHYSYSLYG TTLEQ QYNK PLSDLLIRCI NCQKPLSPEE KQRHLDKKQR FHNIRGRWTG RCMSCSRSSR TRRETQL UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Protein E6 |
-分子 #2: Cellular tumor antigen p53
分子 | 名称: Cellular tumor antigen p53 / 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: 24.64393 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: GSSSVPSQKT YQGSYGFRLG FLHSGTAKSV TCTYSPALNK MFCQLAKTCP VQLWVDSTPP PGTRVRAMAI YKQSQHMTEV VRRCPHHER CSDSDGLAPP QHLIRVEGNL RVEYLDDRNT FRHSVVVPYE PPEVGSDCTT IHYNYMCNSS CMGGMNRRPI L TIITLEDS ...文字列: GSSSVPSQKT YQGSYGFRLG FLHSGTAKSV TCTYSPALNK MFCQLAKTCP VQLWVDSTPP PGTRVRAMAI YKQSQHMTEV VRRCPHHER CSDSDGLAPP QHLIRVEGNL RVEYLDDRNT FRHSVVVPYE PPEVGSDCTT IHYNYMCNSS CMGGMNRRPI L TIITLEDS SGNLLGRNSF EVRVCACPGR DRRTEEENLR KKGEPHHELP PGSTKRALPN NT UniProtKB: P53遺伝子 |
-分子 #3: Ubiquitin-protein ligase E3A
分子 | 名称: Ubiquitin-protein ligase E3A / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO / EC番号: HECT-type E3 ubiquitin transferase |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 104.305281 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAAI KALELYKINA KLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL CREREDYSPL IRVIGRVFSS A EALVQSFR ...文字列: MEKLHQCYWK SGEPQSDDIE ASRMKRAAAK HLIERYYHQL TEGCGNEACT NEFCASCPTF LRMDNNAAAI KALELYKINA KLCDPHPSK KGASSAYLEN SKGAPNNSCS EIKMNKKGAR IDFKDVTYLT EEKVYEILEL CREREDYSPL IRVIGRVFSS A EALVQSFR KVKQHTKEEL KSLQAKDEDK DEDEKEKAAC SAAAMEEDSE ASSSRIGDSS QGDNNLQKLG PDDVSVDIDA IR RVYTRLL SNEKIETAFL NALVYLSPNV ECDLTYHNVY SRDPNYLNLF IIVMENRNLH SPEYLEMALP LFCKAMSKLP LAA QGKLIR LWSKYNADQI RRMMETFQQL ITYKVISNEF NSRNLVNDDD AIVAASKCLK MVYYANVVGG EVDTNHNEED DEEP IPESS ELTLQELLGE ERRNKKGPRV DPLETELGVK TLDCRKPLIP FEEFINEPLN EVLEMDKDYT FFKVETENKF SFMTC PFIL NAVTKNLGLY YDNRIRMYSE RRITVLYSLV QGQQLNPYLR LKVRRDHIID DALVRLEMIA MENPADLKKQ LYVEFE GEQ GVDEGGVSKE FFQLVVEEIF NPDIGMFTYD ESTKLFWFNP SSFETEGQFT LIGIVLGLAI YNNCILDVHF PMVVYRK LM GKKGTFRDLG DSHPVLYQSL KDLLEYEGNV EDDMMITFQI SQTDLFGNPM MYDLKENGDK IPITNENRKE FVNLYSDY I LNKSVEKQFK AFRRGFHMVT NESPLKYLFR PEEIELLICG SRNLDFQALE ETTEYDGGYT RDSVLIREFW EIVHSFTDE QKRLFLQFTT GTDRAPVGGL GKLKMIIAKN GPDTERLPTS HTCFNVLLLP EYSSKEKLKE RLLKAITYAK GFGMLENLYF QGHHHHHHG LNDIFEAQKI EWHE UniProtKB: Ubiquitin-protein ligase E3A |
-分子 #4: ZINC ION
分子 | 名称: ZINC ION / タイプ: ligand / ID: 4 / コピー数: 3 / 式: ZN |
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分子量 | 理論値: 65.409 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
濃度 | 2.15 mg/mL | |||||||||||||||
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緩衝液 | pH: 7 構成要素:
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グリッド | モデル: Quantifoil R1.2/1.3 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY / 支持フィルム - Film thickness: 30 / 前処理 - タイプ: GLOW DISCHARGE / 前処理 - 時間: 60 sec. | |||||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 277.15 K / 装置: FEI VITROBOT MARK IV |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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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: FLOOD BEAM / 撮影モード: BRIGHT FIELDBright-field microscopy / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 1.5 µm |
撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 80.5 e/Å2 |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |