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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by apratoxin F | |||||||||
![]() | Unsharpened map of Apratoxin F bound chimeric Sec complex (whole) | |||||||||
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![]() | Sec61 / translocon / apratoxin / inhibitor / protein translocation / PROTEIN TRANSPORT | |||||||||
機能・相同性 | ![]() Sec62/Sec63 complex / translocon complex / cytosol to endoplasmic reticulum transport / endoplasmic reticulum Sec complex / pronephric nephron development / endoplasmic reticulum quality control compartment / rough endoplasmic reticulum membrane / cotranslational protein targeting to membrane / Ssh1 translocon complex / Sec61 translocon complex ...Sec62/Sec63 complex / translocon complex / cytosol to endoplasmic reticulum transport / endoplasmic reticulum Sec complex / pronephric nephron development / endoplasmic reticulum quality control compartment / rough endoplasmic reticulum membrane / cotranslational protein targeting to membrane / Ssh1 translocon complex / Sec61 translocon complex / protein targeting to ER / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / filamentous growth / SRP-dependent cotranslational protein targeting to membrane / SRP-dependent cotranslational protein targeting to membrane, translocation / signal sequence binding / post-translational protein targeting to membrane, translocation / endoplasmic reticulum organization / nuclear inner membrane / epidermal growth factor binding / retrograde protein transport, ER to cytosol / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / SRP-dependent cotranslational protein targeting to membrane / protein transmembrane transporter activity / ERAD pathway / guanyl-nucleotide exchange factor activity / cell periphery / calcium channel activity / ribosome binding / ER-Phagosome pathway / endoplasmic reticulum membrane / endoplasmic reticulum / mitochondrion / RNA binding / membrane / cytosol 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.54 Å | |||||||||
![]() | Park E / Itskanov S | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: A common mechanism of Sec61 translocon inhibition by small molecules. 著者: Samuel Itskanov / Laurie Wang / Tina Junne / Rumi Sherriff / Li Xiao / Nicolas Blanchard / Wei Q Shi / Craig Forsyth / Dominic Hoepfner / Martin Spiess / Eunyong Park / ![]() ![]() ![]() 要旨: The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural ...The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design. | |||||||||
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構造の表示
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-EMDBアーカイブ
マップデータ | ![]() | 59.6 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 25.1 KB 25.1 KB | 表示 表示 | ![]() |
画像 | ![]() | 65 KB | ||
その他 | ![]() ![]() ![]() | 32.4 MB 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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注釈 | Unsharpened map of Apratoxin F bound chimeric Sec complex (whole) | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.05 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
-追加マップ: Sharpened map of Apratoxin F bound chimeric Sec complex (whole)
ファイル | emd_29610_additional_1.map | ||||||||||||
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注釈 | Sharpened map of Apratoxin F bound chimeric Sec complex (whole) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half ma A of Apratoxin F bound chimeric Sec complex (whole)
ファイル | emd_29610_half_map_1.map | ||||||||||||
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注釈 | Half ma A of Apratoxin F bound chimeric Sec complex (whole) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half ma B of Apratoxin F bound chimeric Sec complex (whole)
ファイル | emd_29610_half_map_2.map | ||||||||||||
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注釈 | Half ma B of Apratoxin F bound chimeric Sec complex (whole) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : A human-yeast chimeric Sec complex treated with apratoxin F
全体 | 名称: A human-yeast chimeric Sec complex treated with apratoxin F |
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要素 |
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-超分子 #1: A human-yeast chimeric Sec complex treated with apratoxin F
超分子 | 名称: A human-yeast chimeric Sec complex treated with apratoxin F タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: ![]() |
-分子 #1: Human Sec61 gamma subunit
分子 | 名称: Human Sec61 gamma subunit / タイプ: protein_or_peptide / ID: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MDQVMQFVEP SRQFVKDSIR LVKRCTKPDR KEFQKIAMAT AIGFAIMGFI GFFVKLIHIP INNIIVGG UniProtKB: Protein transport protein Sec61 subunit gamma |
-分子 #2: Human Sec61 beta subunit
分子 | 名称: Human Sec61 beta subunit / タイプ: protein_or_peptide / ID: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MPGPTPSGTN VGSSGRSPSK AVAARAAGST VRQRKNASCG TRSAGRTTSA GTGGMWRFYT EDSPGLKVGP VPVLVMSLLF IASVFMLHI WGKYTRS UniProtKB: Protein transport protein Sec61 subunit beta |
-分子 #3: Human Sec61 alpha subunit (loop mutant)
分子 | 名称: Human Sec61 alpha subunit (loop mutant) / タイプ: protein_or_peptide / ID: 3 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MAIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PFYWMRVILA SNRGTLMELG ISPIVTSGL IMQLLAGAKI IEVGDTPKDR ALFNGAQKLF GMIITIGQSI VYVMTGMYGD PSEMGAGICL LITIQLFVAG L IVLLLDEL ...文字列: MAIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PFYWMRVILA SNRGTLMELG ISPIVTSGL IMQLLAGAKI IEVGDTPKDR ALFNGAQKLF GMIITIGQSI VYVMTGMYGD PSEMGAGICL LITIQLFVAG L IVLLLDEL LQKGYGLGSG ISLFIATNIC ETIVWKAFSP TTVNTGRGME FEGAIIALFH LLATRTDKVR ALREAFYRQN LP NLMNLIA TIFVFAVVIY FQGFRYELPI RSTKVRGQIG IYPIKLFYTS NIPIILQSAL VSNLYVISQM LSARFSGNLL VSL LGTWSD TSSGGPARAY PVGGLCYYLS PPESFGSVLE DPVHAVVYIV FMLGSCAFFS KTWIEVSGSS PRDIAKQFKD QGMV INGKR ETSIYRELKK IIPTAAAFGG LCIGALSVLA DFLGAIGSGT GILLAVTIIY QYFEIFVKEQ SEVGSMGALL F UniProtKB: Protein transport protein Sec61 subunit alpha isoform 1 |
-分子 #4: Yeast Sec71
分子 | 名称: Yeast Sec71 / タイプ: protein_or_peptide / ID: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MSEFNETKFS NNGTFFETEE PIVETKSISV YTPLIYVFIL VVSLVMFASS YRKKQAKKIS EQPSIFDEND AHDLYFQIKE MSENEKIHEK VLKAALLNRG AESVRRSLKL KELAPQINLL YKNGSIGEDY WKRFETEVKL IELEFKDTLQ EAERLQPGWV QLFVMVCKEI ...文字列: MSEFNETKFS NNGTFFETEE PIVETKSISV YTPLIYVFIL VVSLVMFASS YRKKQAKKIS EQPSIFDEND AHDLYFQIKE MSENEKIHEK VLKAALLNRG AESVRRSLKL KELAPQINLL YKNGSIGEDY WKRFETEVKL IELEFKDTLQ EAERLQPGWV QLFVMVCKEI CFNQALSRRY QSILKRKEVC IKEWELKINN DGRLVN UniProtKB: Translocation protein SEC66 |
-分子 #5: Yeast Sec72
分子 | 名称: Yeast Sec72 / タイプ: protein_or_peptide / ID: 5 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MVTLEYNANS KLITASDAVV ALSTETNIDQ INVLTTSLIG ETNPNFTPQP NEALSKMIKG LFESGMKNLQ QKKLNEALKN VSLAIEMAQR KRAPWEAFAI QLPELHFMLR SKIDLCLILG KHLEALQDLD FLLGTGLIQP DVFVRKADCL LKLRQWEEAR ATCERGLALA ...文字列: MVTLEYNANS KLITASDAVV ALSTETNIDQ INVLTTSLIG ETNPNFTPQP NEALSKMIKG LFESGMKNLQ QKKLNEALKN VSLAIEMAQR KRAPWEAFAI QLPELHFMLR SKIDLCLILG KHLEALQDLD FLLGTGLIQP DVFVRKADCL LKLRQWEEAR ATCERGLALA PEDMKLRALL IETARNLAEY NGE UniProtKB: Translocation protein SEC72 |
-分子 #6: Yeast-human chimeric Sec63
分子 | 名称: Yeast-human chimeric Sec63 / タイプ: protein_or_peptide / ID: 6 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MAGQQFQYDD SGNTFFYFLT SFVGLIVIPM TLLQIYQIFF GANAEDGNSG KSKEFNEEVF KNLNEEYTSD EIKQFRRKFD KNSNKKSKIW SRRNIVLLAG WALFLFLAYK VSKTDREYQE YNPYEVLNLD PGATVAEIKK QYRLLSLKYH PDKGGDEVMF MRIAKAYAAL ...文字列: MAGQQFQYDD SGNTFFYFLT SFVGLIVIPM TLLQIYQIFF GANAEDGNSG KSKEFNEEVF KNLNEEYTSD EIKQFRRKFD KNSNKKSKIW SRRNIVLLAG WALFLFLAYK VSKTDREYQE YNPYEVLNLD PGATVAEIKK QYRLLSLKYH PDKGGDEVMF MRIAKAYAAL TDEESRKNWE EFGNPDGPQA TSFGIALPAW IVDQKNSILV LLVYGLAFMV ILPVVVGSWW YRTQSYTKKG IHNVTASNFV SNLVNYKPSE IVTTDLILHW LSFAHEFKQF FPDLQPTDFE KLLQDHINRR DSGKLNNAKF RIVAKCHSLL HGLLDIACGF RNLDIALGAI NTFKCIVQAV PLTPNCQILQ LPNVDKEHFI TKTGDIHTLG KLFTLEDAKI GEVLGIKDQA KLNETLRVAS HIPNLKIIKA DFLVPGENQV TPSSTPYISL KVLVRSAKQP LIPTSLIPEE NLTEPQDFES QRDPFAMMSK QPLVPYSFAP FFPTKRRGSW CCLVSSQKDG KILQTPIIIE KLSYKNLNDD KDFFDKRIKM DLTKHEKFDI NDWEIGTIKI PLGQPAPETV GDFFFRVIVK STDYFTTDLD ITMNMKVRDS PAVEQVEVYS EEDDEYSTDD DETESDDESD ASDYTDIDTD TEAEDDESPE GAGSNSLEVL FQ UniProtKB: Protein translocation protein SEC63 |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
濃度 | 10 mg/mL | ||||||||||||||||||
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緩衝液 | pH: 7.5 構成要素:
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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 / 装置: FEI VITROBOT MARK IV / 詳細: blot for 4 seconds before plunging. | ||||||||||||||||||
詳細 | Reconsitituted into a peptidisc. Monodisperse peak from a Superose 6 column. |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | エネルギーフィルター - 名称: GIF Quantum LS / エネルギーフィルター - スリット幅: 20 eV |
撮影 | フィルム・検出器のモデル: GATAN K3 (6k 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: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / Cs: 2.7 mm / 最大 デフォーカス(公称値): 1.6 µm / 最小 デフォーカス(公称値): 0.8 µm / 倍率(公称値): 81000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |