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基本情報
登録情報 | データベース: EMDB / ID: EMD-23950 | |||||||||
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タイトル | The insulin receptor ectodomain in complex with four venom hybrid insulins - symmetric conformation | |||||||||
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機能・相同性 | ![]() regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly ...regulation of female gonad development / positive regulation of meiotic cell cycle / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / dendritic spine maintenance / insulin binding / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / PTB domain binding / adrenal gland development / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / activation of protein kinase activity / Insulin processing / neuronal cell body membrane / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / positive regulation of receptor internalization / alpha-beta T cell activation / regulation of embryonic development / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / phosphatidylinositol 3-kinase binding / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / heart morphogenesis / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / dendrite membrane / insulin-like growth factor receptor binding / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / receptor-mediated endocytosis / positive regulation of MAP kinase activity / positive regulation of nitric-oxide synthase activity / learning / positive regulation of cytokine production / caveola / positive regulation of long-term synaptic potentiation / acute-phase response / Regulation of insulin secretion / negative regulation of protein catabolic process / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / receptor protein-tyrosine kinase / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / peptidyl-tyrosine phosphorylation / regulation of synaptic plasticity / vasodilation / hormone activity / cellular response to insulin stimulus / receptor internalization / memory / cellular response to growth factor stimulus / cognition / positive regulation of neuron projection development 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: 4.1 Å | |||||||||
![]() | Blakely AD / Xiong X / Kim JH / Menting J / Schafer IB / Schubert HL / Agrawal R / Gutmann T / Delaine C / Zhang Y ...Blakely AD / Xiong X / Kim JH / Menting J / Schafer IB / Schubert HL / Agrawal R / Gutmann T / Delaine C / Zhang Y / Artik GO / Merriman A / Eckert D / Lawrence MC / Coskun U / Fisher SJ / Forbes BE / Safavi-Hemami H / Hill CP / Chou DHC | |||||||||
資金援助 | 1件
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![]() | ![]() タイトル: Symmetric and asymmetric receptor conformation continuum induced by a new insulin. 著者: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / ...著者: Xiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / Allanah Merriman / Debbie Eckert / Michael C Lawrence / Ünal Coskun / Simon J Fisher / Briony E Forbes / Helena Safavi-Hemami / Christopher P Hill / Danny Hung-Chieh Chou / ![]() ![]() ![]() ![]() 要旨: Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active ...Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. | |||||||||
履歴 |
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構造の表示
ムービー |
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構造ビューア | EMマップ: ![]() ![]() ![]() |
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 | ![]() | 59.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 19.5 KB 19.5 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 8.9 KB | 表示 | ![]() |
画像 | ![]() | 117 KB | ||
マスクデータ | ![]() | 64 MB | ![]() | |
その他 | ![]() ![]() | 59.2 MB 59.2 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 7mqrMC ![]() 7mqoC ![]() 7mqsC 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 ( |
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類似構造データ | |
電子顕微鏡画像生データ | ![]() Data size: 11.7 TB Data #1: Unaligned multi-frame micrographs (40 e-/A2 dose) [micrographs - multiframe] Data #2: unaligned micrographs (60 e-/A2 dose) [micrographs - multiframe]) |
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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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ボクセルのサイズ | X=Y=Z: 1.365 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
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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_23950_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_23950_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 |
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試料の構成要素
-全体 : Insulin receptor ectodomain in complex with insulin analog Vh-Ins...
全体 | 名称: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - whole ectodomain. |
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要素 |
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-超分子 #1: Insulin receptor ectodomain in complex with insulin analog Vh-Ins...
超分子 | 名称: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - whole ectodomain. タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 209 KDa |
-分子 #1: Insulin A chain
分子 | 名称: Insulin A chain / タイプ: protein_or_peptide / ID: 1 / コピー数: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 2.736106 KDa |
配列 | 文字列: GIVEQCCTSI CSLYQLENYC HSLQ |
-分子 #2: Insulin B chain
分子 | 名称: Insulin B chain / タイプ: protein_or_peptide / ID: 2 / コピー数: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 2.537951 KDa |
配列 | 文字列: FVNQHLCGSE LVEALYLVCL ER |
-分子 #3: Isoform Short of Insulin receptor
分子 | 名称: Isoform Short of Insulin receptor / タイプ: protein_or_peptide / ID: 3 / コピー数: 2 / 光学異性体: LEVO / EC番号: receptor protein-tyrosine kinase |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 104.632695 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN ...文字列: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDIC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HSECLGNCSQ PDDPTKCVAC RNFYLDGRCV ET CPPPYYH FQDWRCVNFS FCQDLHHKCK NSRRQGCHQY VIHNNKCIPE CPSGYTMNSS NLLCTPCLGP CPKVCHLLEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG YLKIRRSYAL VSLSFFRKLR LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SYIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPLRSNDPK SQNHPGWLMR GLKPWT QYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSE LF ELDYCLKGLK LPSRTWSPPF ESEDSQKHNQ SEYEDSAGEC CSCPKTDSQI LKELEESSFR KTFEDYLHNV VFVPRPSR K RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAY VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRAT SLAGNGSWTE PTYFYVTDYL DVPSNIA |
-分子 #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 4 / コピー数: 20 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-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
緩衝液 | pH: 8 / 構成要素: (名称: HEPES, Tris) 詳細: Equal parts HBS(50 mM HEPES pH 7.5, 150 mM NaCl ) and TBS (25 mM Tris pH 8.5, 150 mM NaCl) |
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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 |
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 80 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK II |
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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) 検出モード: COUNTING / 平均電子線量: 40.0 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 |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |