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- EMDB-0600: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug... -

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基本情報

登録情報
データベース: EMDB / ID: EMD-0600
タイトルHuman ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
マップデータPF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is sharpened.
試料
  • 複合体: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
機能・相同性
機能・相同性情報


response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / cell-cell adhesion mediated by cadherin / negative regulation of axon extension / cellular response to indole-3-methanol / flotillin complex / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response ...response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / cell-cell adhesion mediated by cadherin / negative regulation of axon extension / cellular response to indole-3-methanol / flotillin complex / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / embryonic brain development / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / eukaryotic 80S initiation complex / protein tyrosine kinase inhibitor activity / Formation of definitive endoderm / negative regulation of protein neddylation / calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules / translation at presynapse / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of respiratory burst involved in inflammatory response / positive regulation of gastrulation / axial mesoderm development / regulation of G1 to G0 transition / negative regulation of formation of translation preinitiation complex / IRE1-RACK1-PP2A complex / nucleolus organization / ribosomal protein import into nucleus / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / response to extracellular stimulus / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / exit from mitosis / protein-DNA complex disassembly / TNFR1-mediated ceramide production / 90S preribosome assembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of DNA repair / negative regulation of RNA splicing / laminin receptor activity / optic nerve development / Adherens junctions interactions / TORC2 complex binding / catenin complex / Apoptotic cleavage of cell adhesion proteins / oxidized purine DNA binding / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / GAIT complex / G1 to G0 transition / neural crest cell differentiation / retinal ganglion cell axon guidance / NF-kappaB complex / rRNA modification in the nucleus and cytosol / negative regulation of phagocytosis / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / cell-cell junction assembly / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / GTPase activating protein binding / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / adherens junction organization / A band / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / alpha-beta T cell differentiation / 顔料 / protein kinase A binding / negative regulation of ubiquitin protein ligase activity / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / apical junction complex / ankyrin binding / Translation initiation complex formation / phagocytic cup / positive regulation of mitochondrial depolarization / response to aldosterone / negative regulation of Wnt signaling pathway / homeostatic process / positive regulation of T cell receptor signaling pathway / lung morphogenesis / macrophage chemotaxis / positive regulation of activated T cell proliferation / fibroblast growth factor binding / negative regulation of cell-cell adhesion / regulation of cell division / cellular response to lithium ion / SARS-CoV-1 modulates host translation machinery / homophilic cell adhesion via plasma membrane adhesion molecules / iron-sulfur cluster binding / ヒドロキシル化 / MTOR / BH3 domain binding / mTORC1-mediated signalling / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA)
類似検索 - 分子機能
Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / カドヘリン / Catenin binding domain superfamily / Ubiquitin-like protein FUBI / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain ...Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / カドヘリン / Catenin binding domain superfamily / Ubiquitin-like protein FUBI / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Cadherin conserved site / Cadherin domain signature. / Cadherin repeats. / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ribosomal protein L30e / Cadherin domain / Cadherins domain profile. / Cadherin-like / Ribosomal protein L28e / Ribosomal protein L2, archaeal-type / Ribosomal L15/L27a, N-terminal / Cadherin-like superfamily / Ribosomal protein L23 / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / : / Ribosomal protein S12e / Small (40S) ribosomal subunit Asc1/RACK1 / metallochaperone-like domain / TRASH domain / Ribosomal protein S19e, conserved site / : / S27a-like superfamily / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein S25 / Ribosomal protein S26e signature. / Ribosomal protein S17e, conserved site / : / Ribosomal protein S2, eukaryotic / Ribosomal protein S30 / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein L29e / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein S8e subdomain, eukaryotes / S25 ribosomal protein / Ribosomal protein L10e, conserved site / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein L10e / Ribosomal protein L27e, conserved site / Ribosomal protein S19A/S15e / Ribosomal protein S21e, conserved site / Ribosomal protein S21e signature. / Ribosomal L29e protein family / Ribosomal protein S30 / Ribosomal protein S3Ae, conserved site / Ribosomal protein S12e signature. / Ribosomal protein S17e / Ribosomal protein S17e-like superfamily / Ribosomal protein S27a / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein S19e / Ribosomal_S19e / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S8e, conserved site / 40S ribosomal protein S11, N-terminal / 40S ribosomal protein S1/3, eukaryotes / Ribosomal protein S6, eukaryotic / Ribosomal protein L24e, conserved site / Ribosomal protein S7e / 40S ribosomal protein S4, C-terminal domain / Ribosomal protein L34e, conserved site / Eukaryotic Ribosomal Protein L27, KOW domain / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal S17 / Ribosomal protein S19e signature. / Ribosomal protein L44e / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal protein L27e / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein L27e superfamily / Ribosomal protein S21e / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal protein S19e / Ribosomal protein S27, zinc-binding domain superfamily / Ribosomal L38e protein family / Ribosomal L22e protein family / Ribosomal protein L23/L25, N-terminal / 40S Ribosomal protein S10 / 60S ribosomal protein L35
類似検索 - ドメイン・相同性
FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Cadherin-1 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Cadherin-1 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 / Large ribosomal subunit protein eL13 / Large ribosomal subunit protein uL16 / Large ribosomal subunit protein uL6 / Large ribosomal subunit protein eL22 / Large ribosomal subunit protein uL4 / Small ribosomal subunit protein eS19 / Large ribosomal subunit protein uL3 / Large ribosomal subunit protein uL13 / Small ribosomal subunit protein eS27 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein eL21 / Large ribosomal subunit protein eL28 / Small ribosomal subunit protein uS4 / Small ribosomal subunit protein uS7 / Small ribosomal subunit protein eS10 / Large ribosomal subunit protein eL29 / Large ribosomal subunit protein eL34 / Large ribosomal subunit protein eL14 / Small ribosomal subunit protein uS10 / Small ribosomal subunit protein eS1 / Large ribosomal subunit protein uL24 / Large ribosomal subunit protein eL15 / Large ribosomal subunit protein eL27 / Large ribosomal subunit protein eL43 / Large ribosomal subunit protein eL37 / Small ribosomal subunit protein eS7 / Small ribosomal subunit protein eS8 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein uS9 / Small ribosomal subunit protein uS11 / Small ribosomal subunit protein uS12 / Small ribosomal subunit protein uS13 / Small ribosomal subunit protein uS14 / Small ribosomal subunit protein uS15 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein eL8 / Small ribosomal subunit protein eS4, X isoform / Large ribosomal subunit protein uL23 / Small ribosomal subunit protein eS6 / Large ribosomal subunit protein uL14 / Small ribosomal subunit protein uS19 / Small ribosomal subunit protein eS24 / Small ribosomal subunit protein eS25 / Small ribosomal subunit protein eS26 / Small ribosomal subunit protein eS28 / Ubiquitin-like FUBI-ribosomal protein eS30 fusion protein / Large ribosomal subunit protein eL30 / Large ribosomal subunit protein eL39 / Large ribosomal subunit protein eL31 / Large ribosomal subunit protein eL32 / Large ribosomal subunit protein uL5 / Large ribosomal subunit protein uL2 / Small ribosomal subunit protein eS32 / Ubiquitin-ribosomal protein eS31 fusion protein / Ubiquitin-ribosomal protein eL40 fusion protein / Large ribosomal subunit protein eL38 / Small ribosomal subunit protein eS21 / Small ribosomal subunit protein RACK1 / Large ribosomal subunit protein eL24 / Large ribosomal subunit protein eL42 / Large ribosomal subunit protein eL19 / Large ribosomal subunit protein eL20 / Large ribosomal subunit protein eL6 / Large ribosomal subunit protein eL18 / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein eL36
類似検索 - 構成要素
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: 3.0 Å
データ登録者Li W / Cate JHD
資金援助 米国, 1件
OrganizationGrant number国
National Institutes of Health/National Human Genome Research InstituteR01-GM065050 米国
引用ジャーナル: Nat Struct Mol Biol / 年: 2019
タイトル: Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.
著者: Wenfei Li / Fred R Ward / Kim F McClure / Stacey Tsai-Lan Chang / Elizabeth Montabana / Spiros Liras / Robert G Dullea / Jamie H D Cate /
要旨: The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ...The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest.
履歴
登録2019年2月21日-
ヘッダ(付随情報) 公開2019年3月20日-
マップ公開2019年3月20日-
更新2019年6月19日-
現状2019年6月19日処理サイト: RCSB / 状態: 公開

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構造の表示

ムービー
  • 表面図（断面を密度値に従い着色）
  • 表面レベル: 0.02
  • UCSF Chimeraによる作画
  • ダウンロード
  • 表面図（高さに従い着色）
  • 表面レベル: 0.02
  • UCSF Chimeraによる作画
  • ダウンロード
  • あてはめたモデルとの重ね合わせ
  • 原子モデル: PDB-6ole
  • 表面レベル: 0.02
  • UCSF Chimeraによる作画
  • ダウンロード
ムービービューア
構造ビューアEMマップ:
SurfViewMolmilJmol/JSmol
添付画像

emd_0600.png

ダウンロードとリンク

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マップ

ファイルダウンロード / ファイル: emd_0600.map.gz / 形式: CCP4 / 大きさ: 244.1 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is sharpened.
ボクセルのサイズX=Y=Z: 1.15 Å
密度
表面レベルBy EMDB: 0.02 / ムービー #1: 0.02
最小 - 最大-0.06671343 - 0.14892814
平均 (標準偏差)0.00041651924 (±0.0066053597)
対称性空間群: 1
詳細

EMDB XML:

マップ形状
Axis orderXYZ
Origin000
サイズ400400400
Spacing400400400
セルA=B=C: 460.0 Å
α=β=γ: 90.0 °

CCP4マップ ヘッダ情報:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z460.000460.000460.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0670.1490.000

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添付データ

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追加マップ: PF846 stalled human ribosome nascent chain complex (CDH1-RNC)...

ファイルemd_0600_additional.map
注釈PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is not sharpened.
投影像・断面図
軸ZYX

投影像

断面 (1/2)
密度ヒストグラム

ヒストグラム

ヒストグラム (対数)

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ハーフマップ: Half map of PF846 stalled human ribosome nascent...

ファイルemd_0600_half_map_1.map
注釈Half map of PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA.
投影像・断面図
軸ZYX

投影像

断面 (1/2)
密度ヒストグラム

ヒストグラム

ヒストグラム (対数)

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ハーフマップ: Half map of PF846 stalled human ribosome nascent...

ファイルemd_0600_half_map_2.map
注釈Half map of PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA.
投影像・断面図
軸ZYX

投影像

断面 (1/2)
密度ヒストグラム

ヒストグラム

ヒストグラム (対数)

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試料の構成要素

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全体 : Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug...

全体名称: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
要素
  • 複合体: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA

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超分子 #1: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug...

超分子名称: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1
由来(天然)生物種: Homo sapiens (ヒト)
組換発現生物種: Homo sapiens (ヒト) / 組換細胞: HeLa
分子量理論値: 4.3 MDa

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実験情報

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構造解析

手法クライオ電子顕微鏡法
解析単粒子再構成法
試料の集合状態particle

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試料調製

緩衝液pH: 7.8
グリッド詳細: unspecified
凍結凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 277 K

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電子顕微鏡法

顕微鏡FEI TITAN KRIOS
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
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: 50.0 e/Å2
実験機器
モデル: Titan Krios / 画像提供: FEI Company

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画像解析

初期 角度割当タイプ: ANGULAR RECONSTITUTION
最終 角度割当タイプ: ANGULAR RECONSTITUTION
最終 再構成解像度のタイプ: BY AUTHOR / 解像度: 3.0 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 731100
FSC曲線 (解像度の算出)

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原子モデル構築 1

精密化空間: REAL / 温度因子: 71
得られたモデル

PDB-6ole:
Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP and PE tRNAs

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