+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-36326 | |||||||||||||||||||||||||||
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タイトル | Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide15-bound human GLP-1R-Gs complex | |||||||||||||||||||||||||||
マップデータ | ||||||||||||||||||||||||||||
試料 |
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キーワード | G protein-coupled receptor / ligand recognition / receptor activation / unimolecular dual agonist / STRUCTURAL PROTEIN | |||||||||||||||||||||||||||
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 / 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 / post-translational protein targeting to membrane, translocation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / response to psychosocial stress / photoreceptor outer segment membrane / 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 / photoreceptor outer segment / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / adenylate cyclase-activating G protein-coupled receptor signaling pathway / transmembrane signaling receptor activity / 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 / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / cellular response to hypoxia / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / 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 / membrane / plasma membrane / cytoplasm 類似検索 - 分子機能 | |||||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) / Rattus norvegicus (ドブネズミ) / synthetic construct (人工物) / Bos taurus (ウシ) / Escherichia coli (大腸菌) | |||||||||||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.46 Å | |||||||||||||||||||||||||||
データ登録者 | Yang L / Zhou QT / Dai AT / Zhao FH / Chang RL / Ying TL / Wu BL / Yang DH / Wang MW / Cong ZT | |||||||||||||||||||||||||||
資金援助 | 中国, 8件
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引用 | ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Structural analysis of the dual agonism at GLP-1R and GCGR. 著者: Yang Li / Qingtong Zhou / Antao Dai / Fenghui Zhao / Rulue Chang / Tianlei Ying / Beili Wu / Dehua Yang / Ming-Wei Wang / Zhaotong Cong / 要旨: Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They ...Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously. | |||||||||||||||||||||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_36326.map.gz | 32.8 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-36326-v30.xml emd-36326.xml | 21.3 KB 21.3 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_36326.png | 90.7 KB | ||
Filedesc metadata | emd-36326.cif.gz | 6.6 KB | ||
その他 | emd_36326_half_map_1.map.gz emd_36326_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-36326 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36326 | 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_36326.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.071 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_36326_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: #1
ファイル | emd_36326_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 : Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide 15-boun...
全体 | 名称: Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide 15-bound human GLP-1R-Gs complex |
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要素 |
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-超分子 #1: Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide 15-boun...
超分子 | 名称: Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide 15-bound human GLP-1R-Gs complex タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: all |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
分子 | 名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 41.401863 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: SAEDKAAVER SKMIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI YHVNGYSEEE CKQYKAVVYS NTIQSIIAII RAMGRLKID FGDSARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS GVQACFNRSR EYQLNDSAAY YLNDLDRIAQ P NYIPTQQD ...文字列: SAEDKAAVER SKMIEKQLQK DKQVYRATHR LLLLGADNSG KSTIVKQMRI YHVNGYSEEE CKQYKAVVYS NTIQSIIAII RAMGRLKID FGDSARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS GVQACFNRSR EYQLNDSAAY YLNDLDRIAQ P NYIPTQQD VLRTRVKTSG IFETKFQVDK VNFHMFDVGA QRDERRKWIQ CFNDVTAIIF VVDSSDYNRL QEALNDFKSI WN NRWLRTI SVILFLNKQD LLAEKVLAGK SKIEDYFPEF ARYTTPEDAT PEPGEDPRVT RAKYFIRDEF LRISTASGDG RHY CYPHFT CSVDTENIRR VFNDCRDIIQ RMHLRQYELL |
-分子 #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Rattus norvegicus (ドブネズミ) |
分子量 | 理論値: 37.198656 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD ...文字列: ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLIIW DSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF LDDNQIVTSS G DTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FA TGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHDNRVSCLG VTD DGMAVA TGSWDSFLKI WN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: Peptide 15
分子 | 名称: Peptide 15 / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: synthetic construct (人工物) |
分子量 | 理論値: 3.385689 KDa |
配列 | 文字列: HSQGTFTSDY SKYLDEQAAK EFIAWLMNT |
-分子 #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Bos taurus (ウシ) |
分子量 | 理論値: 6.261229 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: TASIAQARKL VEQLKMEANI DRIKVSKAAA DLMAYCEAHA KEDPLLTPVP ASENPFR UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #5: Nanobody 35
分子 | 名称: Nanobody 35 / タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Escherichia coli (大腸菌) |
分子量 | 理論値: 13.711284 KDa |
組換発現 | 生物種: Escherichia coli (大腸菌) |
配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTV |
-分子 #6: Glucagon-like peptide 1 receptor
分子 | 名称: Glucagon-like peptide 1 receptor / タイプ: protein_or_peptide / ID: 6 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 46.130492 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: VSLWETVQKW REYRRQCQRS LTEDPPPATD LFCNRTFDEY ACWPDGEPGS FVNVSCPWYL PWASSVPQGH VYRFCTAEGL WLQKDNSSL PWRDLSECEE SKRGERSSPE EQLLFLYIIY TVGYALSFSA LVIASAILLG FRHLHCTRNY IHLNLFASFI L RALSVFIK ...文字列: VSLWETVQKW REYRRQCQRS LTEDPPPATD LFCNRTFDEY ACWPDGEPGS FVNVSCPWYL PWASSVPQGH VYRFCTAEGL WLQKDNSSL PWRDLSECEE SKRGERSSPE EQLLFLYIIY TVGYALSFSA LVIASAILLG FRHLHCTRNY IHLNLFASFI L RALSVFIK DAALKWMYST AAQQHQWDGL LSYQDSLSCR LVFLLMQYCV AANYYWLLVE GVYLYTLLAF SVLSEQWIFR LY VSIGWGV PLLFVVPWGI VKYLYEDEGC WTRNSNMNYW LIIRLPILFA IGVNFLIFVR VICIVVSKLK ANLMCKTDIK CRL AKSTLT LIPLLGTHEV IFAFVMDEHA RGTLRFIKLF TELSFTSFQG LMVAILYCFV NNEVQLEFRK SWERWRLE UniProtKB: Glucagon-like peptide 1 receptor |
-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 |
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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: 80.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: OTHER |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.2 µm / 最小 デフォーカス(公称値): 1.2 µm |
-画像解析
初期モデル | モデルのタイプ: PDB ENTRY PDBモデル - PDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.46 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 1252175 |
初期 角度割当 | タイプ: OTHER |
最終 角度割当 | タイプ: OTHER |