+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-30866 | |||||||||
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タイトル | Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 receptor-Gs complex | |||||||||
マップデータ | ||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor ...glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / negative regulation of execution phase of apoptosis / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / post-translational protein targeting to membrane, translocation / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / feeding behavior / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of heart contraction / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / activation of adenylate cyclase activity / response to psychosocial stress / positive regulation of calcium ion import / cellular response to glucagon stimulus / positive regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of insulin secretion / peptide hormone binding / photoreceptor outer segment / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of gluconeogenesis / cardiac muscle cell apoptotic process / protein kinase A signaling / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / hormone activity / Glucagon signaling in metabolic regulation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / positive regulation of peptidyl-serine phosphorylation / GTPase binding / glucose homeostasis / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / cell body / G alpha (s) signalling events / G alpha (q) signalling events / secretory granule lumen 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / synthetic construct (人工物) / Rattus norvegicus (ドブネズミ) / Bos taurus (ウシ) | |||||||||
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 | Cong Z / Chen L / Ma H / Zhou Q / Zou X / Ye C / Dai A / Liu Q / Huang W / Sun X ...Cong Z / Chen L / Ma H / Zhou Q / Zou X / Ye C / Dai A / Liu Q / Huang W / Sun X / Wang X / Xu P / Zhao L / Xia T / Zhong W / Yang D / Xu HE / Zhang Y / Wang M | |||||||||
引用 | ジャーナル: Nat Commun / 年: 2021 タイトル: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. 著者: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong ...著者: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang / 要旨: The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy ...The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. | |||||||||
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_30866.map.gz | 40.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-30866-v30.xml emd-30866.xml | 19 KB 19 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_30866.png | 126 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-30866 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-30866 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_30866_validation.pdf.gz | 464.9 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_30866_full_validation.pdf.gz | 464.5 KB | 表示 | |
XML形式データ | emd_30866_validation.xml.gz | 5.8 KB | 表示 | |
CIF形式データ | emd_30866_validation.cif.gz | 6.6 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30866 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30866 | 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_30866.map.gz / 形式: CCP4 / 大きさ: 42.9 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 1.045 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
-試料の構成要素
+全体 : Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r...
+超分子 #1: Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 r...
+超分子 #2: Guanine nucleotide-binding protein
+超分子 #3: Nanobody-35
+超分子 #4: Glucagon-like peptide 1 receptor
+超分子 #5: Glucagon-like peptide 1
+分子 #1: Glucagon-like peptide 1
+分子 #2: Glucagon-like peptide 1 receptor
+分子 #3: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+分子 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+分子 #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+分子 #6: Nanobody-35
+分子 #7: N-tert-butyl-6,7-bis(chloranyl)quinoxalin-2-amine
+分子 #8: CHOLESTEROL
-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
緩衝液 | pH: 7.4 |
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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) / 検出モード: COUNTING / 平均電子線量: 80.0 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 |
-画像解析
初期モデル | モデルのタイプ: EMDB MAP EMDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 614978 |
初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |