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基本情報
登録情報 | データベース: PDB / ID: 7x8r | ||||||||||||||||||
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タイトル | Cryo-EM structure of the Boc5-bound hGLP-1R-Gs complex | ||||||||||||||||||
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![]() | MEMBRANE PROTEIN / G protein-coupled receptor / glucagon-like peptide-1 receptor / type 2 diabetes mellitus / peptidomimetic agonism | ||||||||||||||||||
機能・相同性 | ![]() glucagon-like peptide 1 receptor activity / glucagon receptor activity / 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 ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / 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) / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment membrane / response to psychosocial stress / regulation of heart contraction / spectrin binding / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / mu-type opioid receptor binding / photoreceptor outer segment / developmental growth / corticotropin-releasing hormone receptor 1 binding / intracellular transport / D1 dopamine receptor binding / Hedgehog 'off' state / 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 / trans-Golgi network membrane / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / 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 activation / 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 / platelet aggregation / 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 / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / positive regulation of cytosolic calcium ion concentration / cell body / G alpha (i) signalling events / fibroblast proliferation / cellular response to hypoxia / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation 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: 2.61 Å | ||||||||||||||||||
![]() | Cong, Z.T. / Zhou, Q.T. / Li, Y. / Chen, L.N. / Zhang, Z.C. / Liang, A.Y. / Liu, Q. / Wu, X.Y. / Dai, A.T. / Xia, T. ...Cong, Z.T. / Zhou, Q.T. / Li, Y. / Chen, L.N. / Zhang, Z.C. / Liang, A.Y. / Liu, Q. / Wu, X.Y. / Dai, A.T. / Xia, T. / Wu, W. / Zhang, Y. / Yang, D.H. / Wang, M.W. | ||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24. 著者: Zhaotong Cong / Qingtong Zhou / Yang Li / Li-Nan Chen / Zi-Chen Zhang / Anyi Liang / Qing Liu / Xiaoyan Wu / Antao Dai / Tian Xia / Wei Wu / Yan Zhang / Dehua Yang / Ming-Wei Wang / ![]() ![]() 要旨: Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require ...Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R. | ||||||||||||||||||
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構造の表示
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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PDBx/mmCIF形式 | ![]() | 200.8 KB | 表示 | ![]() |
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PDB形式 | ![]() | 157.7 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 | ![]() | 880.3 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 895.3 KB | 表示 | |
XML形式データ | ![]() | 34.8 KB | 表示 | |
CIF形式データ | ![]() | 52.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 33057MC ![]() 7x8sC 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 | 類似検索 - 機能・相同性 ![]() |
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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) ![]() ![]() 発現宿主: ![]() ![]() 参照: UniProt: P63092 |
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#2: タンパク質 | 分子量: 37915.496 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 |
#3: タンパク質 | 分子量: 7729.947 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: P59768 |
-抗体 / タンパク質 / 非ポリマー , 3種, 3分子 NR![](data/chem/img/BYI.gif)
![](data/chem/img/BYI.gif)
#4: 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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#5: タンパク質 | 分子量: 50894.816 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: 化合物 | ChemComp-BYI / |
-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 Boc5 and G protein タイプ: COMPLEX / Entity ID: #1-#5 / 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 / 最大 デフォーカス(公称値): 2200 nm / 最小 デフォーカス(公称値): 1200 nm |
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
ソフトウェア | 名称: PHENIX / バージョン: 1.19.1_4122: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.61 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 | ||||||||||||||||||||||||
拘束条件 |
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