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万見- EMDB-21671: CryoEM Structure of the glucagon receptor with a dual-agonist peptide -
+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-21671 | |||||||||||||||||||||||||||||||||
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タイトル | CryoEM Structure of the glucagon receptor with a dual-agonist peptide | |||||||||||||||||||||||||||||||||
マップデータ | postprocessed map | |||||||||||||||||||||||||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 regulation of glycogen metabolic process / glucagon receptor activity / response to starvation / cellular response to glucagon stimulus / exocytosis / peptide hormone binding / hormone-mediated signaling pathway / cellular response to starvation / response to nutrient / guanyl-nucleotide exchange factor activity ...regulation of glycogen metabolic process / glucagon receptor activity / response to starvation / cellular response to glucagon stimulus / exocytosis / peptide hormone binding / hormone-mediated signaling pathway / cellular response to starvation / response to nutrient / guanyl-nucleotide exchange factor activity / generation of precursor metabolites and energy / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / regulation of blood pressure / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / endosome / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / positive regulation of gene expression / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | |||||||||||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) / synthetic construct (人工物) / Lama glama (ラマ) | |||||||||||||||||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.4 Å | |||||||||||||||||||||||||||||||||
データ登録者 | Belousoff MJ / Sexton P / Danev R | |||||||||||||||||||||||||||||||||
資金援助 | 中国, オーストラリア, 日本, 10件
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引用 | ジャーナル: J Biol Chem / 年: 2020 タイトル: Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide. 著者: Rulue Chang / Xin Zhang / Anna Qiao / Antao Dai / Matthew J Belousoff / Qiuxiang Tan / Lijun Shao / Li Zhong / Guangyao Lin / Yi-Lynn Liang / Limin Ma / Shuo Han / Dehua Yang / Radostin Danev ...著者: Rulue Chang / Xin Zhang / Anna Qiao / Antao Dai / Matthew J Belousoff / Qiuxiang Tan / Lijun Shao / Li Zhong / Guangyao Lin / Yi-Lynn Liang / Limin Ma / Shuo Han / Dehua Yang / Radostin Danev / Ming-Wei Wang / Denise Wootten / Beili Wu / Patrick M Sexton / 要旨: Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R-specific agonists for ...Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R-specific agonists for the management of metabolic disease. The dual-agonist, peptide 15 (P15), is a glutamic acid 16 analog of GCG with GLP-1 peptide substitutions between amino acids 17 and 24 that has potency equivalent to those of the cognate peptide agonists at the GCGR and GLP-1R. Here, we have used cryo-EM to solve the structure of an active P15-GCGR-G complex and compared this structure to our recently published structure of the GCGR-G complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane segment 1 (TM1) such that there is increased mobility of the GCGR extracellular domain and at the C terminus of the peptide compared with the GCG-bound receptor. We also observed a distinct conformation of ECL3 and could infer increased mobility of the far N-terminal His-1 residue in the P15-bound structure. These regions of conformational variance in the two peptide-bound GCGR structures were also regions that were distinct between GCGR structures and previously published peptide-bound structures of the GLP-1R, suggesting that greater conformational dynamics may contribute to the increased efficacy of P15 in activation of the GLP-1R compared with GCG. The variable domains in this receptor have previously been implicated in biased agonism at the GLP-1R and could result in altered signaling of P15 at the GCGR compared with GCG. | |||||||||||||||||||||||||||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
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_21671.map.gz | 4.2 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-21671-v30.xml emd-21671.xml | 27 KB 27 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_21671_fsc.xml | 9.2 KB | 表示 | FSCデータファイル |
画像 | emd_21671.png | 42.5 KB | ||
マスクデータ | emd_21671_msk_1.map | 64 MB | マスクマップ | |
その他 | emd_21671_additional.map.gz emd_21671_half_map_1.map.gz emd_21671_half_map_2.map.gz | 49.1 MB 49.9 MB 49.9 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-21671 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21671 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_21671_validation.pdf.gz | 655.9 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_21671_full_validation.pdf.gz | 655.5 KB | 表示 | |
XML形式データ | emd_21671_validation.xml.gz | 15.3 KB | 表示 | |
CIF形式データ | emd_21671_validation.cif.gz | 20.8 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21671 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21671 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「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_21671.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | postprocessed map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 0.83 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
ファイル | emd_21671_msk_1.map | ||||||||||||
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密度ヒストグラム |
-追加マップ: unsharpened map
ファイル | emd_21671_additional.map | ||||||||||||
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注釈 | unsharpened map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: halfmap 1
ファイル | emd_21671_half_map_1.map | ||||||||||||
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注釈 | halfmap 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: halfmap 2
ファイル | emd_21671_half_map_2.map | ||||||||||||
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注釈 | halfmap 2 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
+全体 : Glucagon Receptor complex
+超分子 #1: Glucagon Receptor complex
+超分子 #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
+超分子 #3: Dual-agonist peptide
+超分子 #4: Nanobody 35
+分子 #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+分子 #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+分子 #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+分子 #4: Dual-agonist peptide
+分子 #5: Nanobody35
+分子 #6: Glucagon receptor
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
濃度 | 2.5 mg/mL |
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緩衝液 | pH: 7.4 |
グリッド | モデル: Quantifoil R1.2/1.3 / 材質: COPPER / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY ARRAY |
凍結 | 凍結剤: ETHANE |
-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 K3 (6k x 4k) / 平均電子線量: 58.0 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 |