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基本情報
登録情報 | データベース: PDB / ID: 7fim | ||||||||||||||||||||||||
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タイトル | Cryo-EM structure of the tirzepatide (LY3298176)-bound human GLP-1R-Gs complex | ||||||||||||||||||||||||
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![]() | STRUCTURAL PROTEIN / Cryo-electron microscopy / G protein-coupled receptor / ligand recognition / receptor activation / unimolecular agonist | ||||||||||||||||||||||||
機能・相同性 | ![]() glucagon-like peptide 1 receptor activity / glucagon receptor activity / sensory perception of chemical stimulus / hormone secretion / positive regulation of blood pressure / 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 ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / sensory perception of chemical stimulus / hormone secretion / positive regulation of blood pressure / 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 / 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 / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / post-translational protein targeting to membrane, translocation / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / 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 / response to psychosocial stress / G alpha (i) signalling events / regulation of heart contraction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / mu-type opioid receptor binding / photoreceptor outer segment / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / cellular response to hypoxia / G alpha (s) signalling events / cell population proliferation / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / GTPase activity / dendrite / protein-containing complex binding / GTP binding / membrane / metal ion binding / plasma membrane 類似検索 - 分子機能 | ||||||||||||||||||||||||
生物種 | synthetic construct (人工物)![]() ![]() ![]() ![]() ![]() | ||||||||||||||||||||||||
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: 3.4 Å | ||||||||||||||||||||||||
![]() | Zhao, F.H. / Zhou, Q.T. / Cong, Z.T. / Hang, K.N. / Zou, X.Y. / Zhang, C. / Chen, Y. / Dai, A.T. / Liang, A.Y. / Ming, Q.Q. ...Zhao, F.H. / Zhou, Q.T. / Cong, Z.T. / Hang, K.N. / Zou, X.Y. / Zhang, C. / Chen, Y. / Dai, A.T. / Liang, A.Y. / Ming, Q.Q. / Wang, M. / Chen, L.N. / Xu, P.Y. / Chang, R.L. / Feng, W.B. / Xia, T. / Zhang, Y. / Wu, B.L. / Yang, D.H. / Zhao, L.H. / Xu, H.E. / Wang, M.W. | ||||||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. 著者: Fenghui Zhao / Qingtong Zhou / Zhaotong Cong / Kaini Hang / Xinyu Zou / Chao Zhang / Yan Chen / Antao Dai / Anyi Liang / Qianqian Ming / Mu Wang / Li-Nan Chen / Peiyu Xu / Rulve Chang / Wenbo ...著者: Fenghui Zhao / Qingtong Zhou / Zhaotong Cong / Kaini Hang / Xinyu Zou / Chao Zhang / Yan Chen / Antao Dai / Anyi Liang / Qianqian Ming / Mu Wang / Li-Nan Chen / Peiyu Xu / Rulve Chang / Wenbo Feng / Tian Xia / Yan Zhang / Beili Wu / Dehua Yang / Lihua Zhao / H Eric Xu / Ming-Wei Wang / ![]() 要旨: Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists ...Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20. | ||||||||||||||||||||||||
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構造の表示
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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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ダウンロード
PDBx/mmCIF形式 | ![]() | 218.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 174.2 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 | ![]() | 746.7 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 757.5 KB | 表示 | |
XML形式データ | ![]() | 35.2 KB | 表示 | |
CIF形式データ | ![]() | 54.2 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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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
-Guanine nucleotide-binding protein ... , 3種, 3分子 BAG
#2: タンパク質 | 分子量: 39221.090 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: P54311 |
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#3: タンパク質 | 分子量: 45743.441 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: P04896 |
#5: タンパク質 | 分子量: 7861.143 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: P63212 |
-抗体 / タンパク質 / タンパク質・ペプチド , 3種, 3分子 NRP
#1: 抗体 | 分子量: 15343.019 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: ![]() ![]() |
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#4: タンパク質 | 分子量: 68355.688 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P43220 |
#6: タンパク質・ペプチド | 分子量: 4072.530 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) ![]() |
-詳細
研究の焦点であるリガンドがあるか | Y |
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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: Cryo-EM structure of the human glucagon like peptide 1 receptor in complex with tirzepatide and G protein タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 7.4 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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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: OTHER / 加速電圧: 300 kV / 照射モード: OTHER |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 80 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3次元再構成 | 解像度: 3.4 Å / 解像度の算出法: DIFFRACTION PATTERN/LAYERLINES / 粒子像の数: 125391 / 対称性のタイプ: POINT |