[日本語] English
万見- EMDB-27705: Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 -
+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-27705 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
タイトル | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 | |||||||||
マップデータ | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 | |||||||||
試料 |
| |||||||||
機能・相同性 | 機能・相同性情報 Signaling by Insulin receptor / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of female gonad development ...Signaling by Insulin receptor / yolk / IRS activation / Insulin receptor signalling cascade / Signal attenuation / Insulin receptor recycling / 3-phosphoinositide-dependent protein kinase binding / positive regulation of glycoprotein biosynthetic process / lipoic acid binding / regulation of female gonad development / regulation of hydrogen peroxide metabolic process / positive regulation of meiotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of developmental growth / nuclear lumen / insulin-like growth factor II binding / 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 / PTB domain binding / adrenal gland development / negative regulation of feeding behavior / neuronal cell body membrane / positive regulation of receptor internalization / positive regulation of respiratory burst / amyloid-beta clearance / regulation of embryonic development / insulin receptor substrate binding / positive regulation of glycogen biosynthetic process / epidermis development / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of phosphorylation / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / negative regulation of protein phosphorylation / response to nutrient levels / positive regulation of D-glucose import / animal organ morphogenesis / receptor protein-tyrosine kinase / caveola / cellular response to growth factor stimulus / receptor internalization / male gonad development / recycling endosome membrane / positive regulation of nitric oxide biosynthetic process / late endosome / insulin receptor signaling pathway / nuclear envelope / glucose homeostasis / amyloid-beta binding / protein tyrosine kinase activity / protein phosphatase binding / protein autophosphorylation / positive regulation of MAPK cascade / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein kinase activity / endosome / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / protein domain specific binding / external side of plasma membrane / axon / negative regulation of gene expression / neuronal cell body / positive regulation of cell population proliferation / GTP binding / protein-containing complex binding / protein kinase binding / positive regulation of DNA-templated transcription / ATP binding / membrane / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | Mus musculus (ハツカネズミ) / synthetic construct (人工物) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.5 Å | |||||||||
データ登録者 | Park J / Li J / Mayer JP / Ball KA / Wu JY / Hall C / Accili D / Stowell MHB / Bai XC / Choi E | |||||||||
資金援助 | 米国, 1件
| |||||||||
引用 | ジャーナル: Nat Commun / 年: 2022 タイトル: Activation of the insulin receptor by an insulin mimetic peptide. 著者: Junhee Park / Jie Li / John P Mayer / Kerri A Ball / Jiayi Wu / Catherine Hall / Domenico Accili / Michael H B Stowell / Xiao-Chen Bai / Eunhee Choi / 要旨: Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity ...Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases. | |||||||||
履歴 |
|
-構造の表示
添付画像 |
---|
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_27705.map.gz | 96.2 MB | EMDBマップデータ形式 | |
---|---|---|---|---|
ヘッダ (付随情報) | emd-27705-v30.xml emd-27705.xml | 18.1 KB 18.1 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_27705.png | 24.9 KB | ||
その他 | emd_27705_half_map_1.map.gz emd_27705_half_map_2.map.gz | 80.7 MB 80.7 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-27705 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27705 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_27705_validation.pdf.gz | 679.9 KB | 表示 | EMDB検証レポート |
---|---|---|---|---|
文書・詳細版 | emd_27705_full_validation.pdf.gz | 679.4 KB | 表示 | |
XML形式データ | emd_27705_validation.xml.gz | 13 KB | 表示 | |
CIF形式データ | emd_27705_validation.cif.gz | 15.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27705 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27705 | HTTPS FTP |
-関連構造データ
関連構造データ | 8dtmMC 8dtlC C: 同じ文献を引用 (文献) M: このマップから作成された原子モデル |
---|---|
類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
---|---|
「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_27705.map.gz / 形式: CCP4 / 大きさ: 103 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
注釈 | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 | ||||||||||||||||||||||||||||||||||||
投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.08 Å | ||||||||||||||||||||||||||||||||||||
密度 |
| ||||||||||||||||||||||||||||||||||||
対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
|
-添付データ
-ハーフマップ: Cryo-EM structure of insulin receptor (IR) bound with...
ファイル | emd_27705_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
注釈 | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 -- half map 1 | ||||||||||||
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-ハーフマップ: Cryo-EM structure of insulin receptor (IR) bound with...
ファイル | emd_27705_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
注釈 | Cryo-EM structure of insulin receptor (IR) bound with S597 component 2 -- half map 2 | ||||||||||||
投影像・断面図 |
| ||||||||||||
密度ヒストグラム |
-試料の構成要素
-全体 : Insulin receptor bound with S597 component 2
全体 | 名称: Insulin receptor bound with S597 component 2 |
---|---|
要素 |
|
-超分子 #1: Insulin receptor bound with S597 component 2
超分子 | 名称: Insulin receptor bound with S597 component 2 / タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: all |
---|---|
由来(天然) | 生物種: Mus musculus (ハツカネズミ) |
-分子 #1: Insulin receptor
分子 | 名称: Insulin receptor / タイプ: protein_or_peptide / ID: 1 / コピー数: 2 / 光学異性体: LEVO / EC番号: receptor protein-tyrosine kinase |
---|---|
由来(天然) | 生物種: Mus musculus (ハツカネズミ) |
分子量 | 理論値: 153.232578 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDVC P GTAKGKTN ...文字列: HLYPGEVCPG MDIRNNLTRL HELENCSVIE GHLQILLMFK TRPEDFRDLS FPKLIMITDY LLLFRVYGLE SLKDLFPNLT VIRGSRLFF NYALVIFEMV HLKELGLYNL MNITRGSVRI EKNNELCYLA TIDWSRILDS VEDNYIVLNK DDNEECGDVC P GTAKGKTN CPATVINGQF VERCWTHSHC QKVCPTICKS HGCTAEGLCC HKECLGNCSE PDDPTKCVAC RNFYLDGQCV ET CPPPYYH FQDWRCVNFS FCQDLHFKCR NSRKPGCHQY VIHNNKCIPE CPSGYTMNSS NLMCTPCLGP CPKVCQILEG EKT IDSVTS AQELRGCTVI NGSLIINIRG GNNLAAELEA NLGLIEEISG FLKIRRSYAL VSLSFFRKLH LIRGETLEIG NYSF YALDN QNLRQLWDWS KHNLTITQGK LFFHYNPKLC LSEIHKMEEV SGTKGRQERN DIALKTNGDQ ASCENELLKF SFIRT SFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN VTEFDGQDAC GSNSWTVVDI DPPQRSNDPK SQTPSHPGWL MRGLKP WTQ YAIFVKTLVT FSDERRTYGA KSDIIYVQTD ATNPSVPLDP ISVSNSSSQI ILKWKPPSDP NGNITHYLVY WERQAED SE LFELDYCLKG LKLPSRTWSP PFESDDSQKH NQSEYDDSAS ECCSCPKTDS QILKELEESS FRKTFEDYLH NVVFVPRP S RKRRSLEEVG NVTATTLTLP DFPNVSSTIV PTSQEEHRPF EKVVNKESLV ISGLRHFTGY RIELQACNQD SPDERCSVA AYVSARTMPE AKADDIVGPV THEIFENNVV HLMWQEPKEP NGLIVLYEVS YRRYGDEELH LCVSRKHFAL ERGCRLRGLS PGNYSVRVR ATSLAGNGSW TEPTYFYVTD YLDVPSNIAK IIIGPLIFVF LFSVVIGSIY LFLRKRQPDG PMGPLYASSN P EYLSASDV FPSSVYVPDE WEVPREKITL LRELGQGSFG MVYEGNAKDI IKGEAETRVA VKTVNESASL RERIEFLNEA SV MKGFTCH HVVRLLGVVS KGQPTLVVME LMAHGDLKSH LRSLRPDAEN NPGRPPPTLQ EMIQMTAEIA DGMAYLNAKK FVH RDLAAR NCMVAHDFTV KIGDFGMTRD IYETDYYRKG GKGLLPVRWM SPESLKDGVF TASSDMWSFG VVLWEITSLA EQPY QGLSN EQVLKFVMDG GYLDPPDNCP ERLTDLMRMC WQFNPKMRPT FLEIVNLLKD DLHPSFPEVS FFYSEENKAP ESEEL EMEF EDMENVPLDR SSHCQREEAG GREGGSSLSI KRTYDEHIPY THMNGGKKNG RVLTLPRSNP S |
-分子 #2: Insulin mimetic peptide S597 component 2
分子 | 名称: Insulin mimetic peptide S597 component 2 / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
---|---|
由来(天然) | 生物種: synthetic construct (人工物) |
分子量 | 理論値: 2.286474 KDa |
配列 | 文字列: SLEEEWAQIE CEVYGRGCPS |
-実験情報
-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 |
-試料調製
濃度 | 6 mg/mL |
---|---|
緩衝液 | pH: 7.4 |
凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
---|---|
特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum / 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 BIOQUANTUM (6k x 4k) 平均電子線量: 60.0 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 / 最大 デフォーカス(公称値): 2.6 µm / 最小 デフォーカス(公称値): 1.6 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
+画像解析
-原子モデル構築 1
精密化 | プロトコル: RIGID BODY FIT |
---|---|
得られたモデル | PDB-8dtm: |