+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-21994 | ||||||||||||||||||
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タイトル | Non peptide agonist PF-06882961, bound to Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
マップデータ | Post-processed consensus map | ||||||||||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / regulation of heart contraction / activation of adenylate cyclase activity / response to psychosocial stress / peptide hormone binding / cAMP-mediated signaling ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / regulation of heart contraction / activation of adenylate cyclase activity / response to psychosocial stress / peptide hormone binding / cAMP-mediated signaling / negative regulation of blood pressure / adenylate cyclase-activating 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 / 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / 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 / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / 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 / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | Homo sapiens (ヒト) / 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: 2.5 Å | ||||||||||||||||||
データ登録者 | Belousoff MJ / Zhang X / Danev R | ||||||||||||||||||
資金援助 | オーストラリア, 5件
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引用 | ジャーナル: Mol Cell / 年: 2020 タイトル: Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. 著者: Xin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / Tin T Truong / Sheng Yu Ang / Christina Rye Underwood / Thomas Egebjerg / Petr Šenel / Gregory D Stewart / Yi-Lynn Liang ...著者: Xin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / Tin T Truong / Sheng Yu Ang / Christina Rye Underwood / Thomas Egebjerg / Petr Šenel / Gregory D Stewart / Yi-Lynn Liang / Alisa Glukhova / Hari Venugopal / Arthur Christopoulos / Sebastian G B Furness / Laurence J Miller / Steffen Reedtz-Runge / Christopher J Langmead / David E Gloriam / Radostin Danev / Patrick M Sexton / Denise Wootten / 要旨: Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. ...Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs. #1: ジャーナル: Biorxiv / 年: 2020 タイトル: Differential GLP-1R binding and activation by peptide and non-peptide agonists 著者: Zhang X / Belousoff MJ / Zhao P / Ang SY / Truong TT / Kooistra AJ / Underwood CR / Egebjerg T / Stewart GD / Liang YL / Glukhova A / Venugopal H / Christopoulos A / Furness SGB / Miller LJ / ...著者: Zhang X / Belousoff MJ / Zhao P / Ang SY / Truong TT / Kooistra AJ / Underwood CR / Egebjerg T / Stewart GD / Liang YL / Glukhova A / Venugopal H / Christopoulos A / Furness SGB / Miller LJ / Runge SR / Gloriam DE / Langmead CJ / Danev R / Sexton PM / Wootten D | ||||||||||||||||||
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_21994.map.gz | 85.2 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-21994-v30.xml emd-21994.xml | 33.8 KB 33.8 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_21994_fsc.xml | 10.2 KB | 表示 | FSCデータファイル |
画像 | emd_21994.png | 43.5 KB | ||
マスクデータ | emd_21994_msk_1.map | 91.1 MB | マスクマップ | |
その他 | emd_21994_additional_1.map.gz emd_21994_additional_2.map.gz emd_21994_additional_3.map.gz emd_21994_additional_4.map.gz emd_21994_half_map_1.map.gz emd_21994_half_map_2.map.gz | 59.2 MB 84.5 MB 81 MB 71.5 MB 71.9 MB 71.8 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-21994 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21994 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_21994_validation.pdf.gz | 846.1 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_21994_full_validation.pdf.gz | 845.7 KB | 表示 | |
XML形式データ | emd_21994_validation.xml.gz | 17.4 KB | 表示 | |
CIF形式データ | emd_21994_validation.cif.gz | 22.9 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21994 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21994 | 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_21994.map.gz / 形式: CCP4 / 大きさ: 91.1 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Post-processed consensus 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_21994_msk_1.map | ||||||||||||
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密度ヒストグラム |
-追加マップ: Local resolution filtered map
ファイル | emd_21994_additional_1.map | ||||||||||||
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注釈 | Local resolution filtered map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Focussed refinement on Receptor
ファイル | emd_21994_additional_2.map | ||||||||||||
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注釈 | Focussed refinement on Receptor | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Focussed refinment on alpha helical domain of G-alpha
ファイル | emd_21994_additional_3.map | ||||||||||||
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注釈 | Focussed refinment on alpha helical domain of G-alpha | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Unsharpened consensus map
ファイル | emd_21994_additional_4.map | ||||||||||||
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注釈 | Unsharpened consensus 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: #1
ファイル | emd_21994_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_21994_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 |
-試料の構成要素
+全体 : PF-06882961:GLP-1R:Gs Complex
+超分子 #1: PF-06882961:GLP-1R:Gs Complex
+超分子 #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
+超分子 #3: Nanobody35
+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: Nanobody35
+分子 #5: Glucagon-like peptide 1 receptor
+分子 #6: 2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-...
+分子 #7: water
-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 | 3.0 mg/mL |
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緩衝液 | pH: 7.4 |
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 |
-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: SPOT SCAN / 撮影モード: BRIGHT FIELD |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |