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基本情報
登録情報 | データベース: PDB / ID: 7mqs | ||||||
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タイトル | The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation | ||||||
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![]() | HORMONE / TOXIN / insulin / receptor / venom / cone snail | ||||||
機能・相同性 | ![]() negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / 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 / Insulin processing / regulation of protein secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / 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 / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / positive regulation of glycolytic process / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / Regulation of insulin secretion / endosome lumen / positive regulation of protein secretion / positive regulation of glucose import / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin-like growth factor receptor binding / wound healing / insulin receptor binding / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / receptor protein-tyrosine kinase / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / regulation of protein localization / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / protease binding / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.4 Å | ||||||
![]() | Blakely, A.D. / Xiong, X. / Kim, J.H. / Menting, J. / Schafer, I.B. / Schubert, H.L. / Agrawal, R. / Gutmann, T. / Delaine, C. / Zhang, Y. ...Blakely, A.D. / Xiong, X. / Kim, J.H. / Menting, J. / Schafer, I.B. / Schubert, H.L. / Agrawal, R. / Gutmann, T. / Delaine, C. / Zhang, Y. / Artik, G.O. / Merriman, A. / Eckert, D. / Lawrence, M.C. / Coskun, U. / Fisher, S.J. / Forbes, B.E. / Safavi-Hemami, H. / Hill, C.P. / Chou, D.H.C. | ||||||
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. | ||||||
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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PDBx/mmCIF形式 | ![]() | 315.3 KB | 表示 | ![]() |
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PDB形式 | ![]() | 257.9 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.2 MB | 表示 | |
XML形式データ | ![]() | 59.4 KB | 表示 | |
CIF形式データ | ![]() | 88.7 KB | 表示 | |
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 | ![]() 23951MC ![]() 7mqoC ![]() 7mqrC C: 同じ文献を引用 ( M: このデータのモデリングに利用したマップデータ |
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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
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 104632.695 Da / 分子数: 2 / 断片: Ectodomain, UNP residues 28-943 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #2: タンパク質・ペプチド | 分子量: 2736.106 Da / 分子数: 3 / Mutation: N21H / 由来タイプ: 合成 / 由来: (合成) ![]() #3: タンパク質・ペプチド | 分子量: 2537.951 Da / 分子数: 3 / Mutation: H10E, G20L / 由来タイプ: 合成 / 由来: (合成) ![]() 配列の詳細 | Elongated Insulin chain A was modified to contain three additional C-terminal residues (SQL) | |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Insulin receptor ectodomain in complex with insulin analog Vh-Ins-HSLQ - asymmetric conformation. タイプ: COMPLEX / Entity ID: all / 由来: MULTIPLE SOURCES | |||||||||
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分子量 | 値: 0.209 MDa / 実験値: NO | |||||||||
由来(天然) | 生物種: ![]() | |||||||||
由来(組換発現) | 生物種: ![]() | |||||||||
緩衝液 | pH: 8 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) | |||||||||
緩衝液成分 |
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試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||
試料支持 | グリッドのタイプ: Quantifoil R1.2/1.3 | |||||||||
急速凍結 | 装置: FEI VITROBOT MARK II / 凍結剤: ETHANE / 湿度: 80 % / 凍結前の試料温度: 277 K |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 40 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.19.1_4122: / 分類: 精密化 | |||||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 4.4 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 43457 / 対称性のタイプ: POINT | |||||||||||||||||||||||||||||||||||
精密化 | 交差検証法: NONE 立体化学のターゲット値: GeoStd + Monomer Library + CDL v1.2 | |||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 200.72 Å2 | |||||||||||||||||||||||||||||||||||
拘束条件 |
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