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基本情報
登録情報 | データベース: PDB / ID: 6x18 | ||||||||||||||||||
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タイトル | GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Receptor | ||||||||||||||||||
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![]() | MEMBRANE PROTEIN / G-coupled protein receptor / GPCR | ||||||||||||||||||
機能・相同性 | ![]() 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 / post-translational protein targeting to membrane, translocation / feeding behavior / response to psychosocial stress / regulation of heart contraction ...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 / post-translational protein targeting to membrane, translocation / feeding behavior / response to psychosocial stress / regulation of heart contraction / positive regulation of calcium ion import / cellular response to glucagon stimulus / response to starvation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / PKA activation in glucagon signalling / regulation of insulin secretion / hair follicle placode formation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / developmental growth / D1 dopamine receptor binding / intracellular transport / Synthesis, secretion, and deacylation of Ghrelin / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / beta-2 adrenergic receptor binding / positive regulation of gluconeogenesis / protein kinase A signaling / adenylate cyclase activator activity / negative regulation of blood pressure / cAMP-mediated signaling / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / platelet aggregation / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / transmembrane signaling receptor activity / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of peptidyl-serine phosphorylation / GTPase binding / retina development in camera-type eye / glucose homeostasis / Ca2+ pathway / positive regulation of cold-induced thermogenesis / 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 / secretory granule lumen / Ras protein signal transduction 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | ![]() ![]() ![]() | ||||||||||||||||||
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: 2.1 Å | ||||||||||||||||||
![]() | Belousoff, M.J. / Zhang, X. / Danev, R. | ||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() 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: ![]() タイトル: Differential GLP-1R binding and activation by peptide and non-peptide agonists 著者: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / ...著者: Zhang, X. / Belousoff, M.J. / Zhao, P. / Ang, S.Y. / Truong, T.T. / Kooistra, A.J. / Underwood, C.R. / Egebjerg, T. / Stewart, G.D. / Liang, Y.L. / Glukhova, A. / Venugopal, H. / Christopoulos, A. / Furness, S.G.B. / Miller, L.J. / Runge, S.R. / Gloriam, D.E. / Langmead, C.J. / Danev, R. / Sexton, P.M. / Wootten, D. | ||||||||||||||||||
履歴 |
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構造の表示
ムービー |
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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 | ![]() | 255.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 205.6 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
関連構造データ | ![]() 21992MC ![]() 6x19C ![]() 6x1aC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | |
電子顕微鏡画像生データ | ![]() Data size: 1.9 TB Data #1: Non-gain-normalized LZW-TIFF compressed movies of GLP-1R-GLP-1 in a detergent micelle [micrographs - multiframe]) |
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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 ABG
#1: タンパク質 | 分子量: 45683.434 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#2: タンパク質 | 分子量: 37413.863 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
#3: タンパク質 | 分子量: 6375.332 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
-抗体 / タンパク質・ペプチド / タンパク質 / 非ポリマー , 4種, 101分子 NPR![](data/chem/img/HOH.gif)
![](data/chem/img/HOH.gif)
#4: 抗体 | 分子量: 13885.439 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() ![]() |
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#5: タンパク質・ペプチド | 分子量: 3302.648 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) ![]() |
#6: タンパク質 | 分子量: 56748.418 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
#7: 水 | ChemComp-HOH / |
-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 |
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分子量 | 値: 0.120 MDa / 実験値: NO | ||||||||||||||||||||||||
由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.4 | ||||||||||||||||||||||||
試料 | 濃度: 3.5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277 K |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 60 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.16_3549: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 635785 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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