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- EMDB-0597: Structure of a drug-like molecule stalled ribosome nascent chain ... -

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基本情報

登録情報
データベース: EMDB / ID: EMD-0597
タイトルStructure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRAN and PE tRNA
マップデータPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened.
試料
  • 複合体: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA
機能・相同性
機能・相同性情報


negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding ...negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / signaling receptor inhibitor activity / LDL clearance / positive regulation of low-density lipoprotein particle receptor catabolic process / lipoprotein metabolic process / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / embryonic brain development / eukaryotic 80S initiation complex / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of protein neddylation / protein tyrosine kinase inhibitor activity / translation at presynapse / positive regulation of respiratory burst involved in inflammatory response / axial mesoderm development / very-low-density lipoprotein particle receptor binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / negative regulation of formation of translation preinitiation complex / nucleolus organization / ribosomal protein import into nucleus / IRE1-RACK1-PP2A complex / : / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / 90S preribosome assembly / negative regulation of low-density lipoprotein receptor activity / TNFR1-mediated ceramide production / negative regulation of RNA splicing / negative regulation of DNA repair / negative regulation of receptor internalization / TORC2 complex binding / endolysosome membrane / regulation of signaling receptor activity / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / sodium channel inhibitor activity / oxidized purine DNA binding / supercoiled DNA binding / neural crest cell differentiation / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / rRNA modification in the nucleus and cytosol / cytoplasmic side of rough endoplasmic reticulum membrane / erythrocyte homeostasis / A band / laminin receptor activity / regulation of G1 to G0 transition / alpha-beta T cell differentiation / exit from mitosis / 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 / protein kinase A binding / protein-DNA complex disassembly / lysosomal transport / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / Translation initiation complex formation / optic nerve development / Ribosomal scanning and start codon recognition / negative regulation of ubiquitin protein ligase activity / ion channel inhibitor activity / pigmentation / mammalian oogenesis stage / positive regulation of mitochondrial depolarization / response to aldosterone / retinal ganglion cell axon guidance / low-density lipoprotein particle receptor binding / G1 to G0 transition / triglyceride metabolic process / homeostatic process / activation-induced cell death of T cells / lung morphogenesis / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / positive regulation of T cell receptor signaling pathway / positive regulation of activated T cell proliferation / iron-sulfur cluster binding / Protein hydroxylation / COPII-coated ER to Golgi transport vesicle / regulation of cell division / negative regulation of peptidyl-serine phosphorylation
類似検索 - 分子機能
Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Proteinase K-like catalytic domain ...Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / 40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Proteinase K-like catalytic domain / Ubiquitin-like protein FUBI / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal protein L28e / Ribosomal L15/L27a, N-terminal / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / Ribosomal protein L23 / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / : / Ribosomal protein S26e signature. / : / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein S21e, conserved site / Ribosomal protein S21e signature. / Ribosomal protein S12e signature. / Serine proteases, subtilase domain profile. / metallochaperone-like domain / Ribosomal protein S12e / TRASH domain / Peptidase S8, subtilisin-related / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Small (40S) ribosomal subunit Asc1/RACK1 / Ribosomal protein S2, eukaryotic / Peptidase S8/S53 domain superfamily / Subtilase family / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Peptidase S8/S53 domain / Ribosomal protein L29e / Ribosomal L29e protein family / 40S Ribosomal protein S10 / S27a-like superfamily / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Plectin/S10, N-terminal / Plectin/S10 domain / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / Ribosomal protein S25 / S25 ribosomal protein / Ribosomal protein S2, eukaryotic/archaeal / : / Ribosomal protein S17e, conserved site / Ribosomal protein S17e signature. / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S8e subdomain, eukaryotes / Ribosomal protein S30 / Ribosomal protein S30 / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein S7e signature. / Ribosomal protein L44e signature. / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein L10e / Ribosomal protein L19, eukaryotic / Ribosomal protein L13e / Ribosomal protein L13e / Ribosomal protein S19e / Ribosomal protein S3Ae, conserved site / Ribosomal protein S19e / Ribosomal protein S3Ae signature. / Ribosomal_S19e / Ribosomal protein S27e signature. / 60S ribosomal protein L18a/ L20, eukaryotes / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein S4e signature. / 40S ribosomal protein S4, C-terminal domain / 40S ribosomal protein S4 C-terminus
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 / 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 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / 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 / Proprotein convertase subtilisin/kexin type 9 / 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: 3.72 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: 0.025
  • 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: 0.025
  • 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-6om7
  • 表面レベル: 0.025
  • 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_0597.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_0597.map.gz / 形式: CCP4 / 大きさ: 303.3 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened.
ボクセルのサイズX=Y=Z: 1.22 Å
密度
表面レベル登録者による: 0.022 / ムービー #1: 0.025
最小 - 最大-0.06245838 - 0.11255686
平均 (標準偏差)0.00044033065 (±0.006970685)
対称性空間群: 1
詳細

EMDB XML:

マップ形状
Axis orderXYZ
Origin000
サイズ430430430
Spacing430430430
セルA=B=C: 524.60004 Å
α=β=γ: 90.0 °

CCP4マップ ヘッダ情報:

modeImage stored as Reals
Å/pix. X/Y/Z1.221.221.22
M x/y/z430430430
origin x/y/z0.0000.0000.000
length x/y/z524.600524.600524.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS430430430
D min/max/mean-0.0620.1130.000

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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 (PCSK9-RNC)...

ファイルemd_0597_additional.map
注釈PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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_0597_half_map_1.map
注釈Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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_0597_half_map_2.map
注釈Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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 : Drug-like molecule PF846 stalled human ribosome nascent chain com...

全体名称: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA
要素
  • 複合体: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA

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超分子 #1: Drug-like molecule PF846 stalled human ribosome nascent chain com...

超分子名称: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA 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: 4 K

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電子顕微鏡法

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

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画像解析

最終 再構成解像度のタイプ: BY AUTHOR / 解像度: 3.72 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 9564
初期 角度割当タイプ: ANGULAR RECONSTITUTION
最終 角度割当タイプ: ANGULAR RECONSTITUTION
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: 91
得られたモデル

PDB-6om7:
Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like small molecule with AA and PE tRNAs

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