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基本情報
登録情報 | データベース: PDB / ID: 7w40 | |||||||||||||||||||||
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タイトル | Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in complex with the agonist Bombesin (6-14) [D-Phe6, beta-Ala11, Phe13, Nle14] and Gq heterotrimers | |||||||||||||||||||||
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![]() | MEMBRANE PROTEIN / GPCR / Gastrin Releasing Peptide Receptor | |||||||||||||||||||||
機能・相同性 | ![]() response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / neuropeptide receptor activity / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / psychomotor behavior / regulation of platelet activation ...response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / neuropeptide receptor activity / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / psychomotor behavior / regulation of platelet activation / phototransduction, visible light / entrainment of circadian clock / neuropeptide binding / G protein-coupled peptide receptor activity / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / motor behavior / action potential / social behavior / : / carbohydrate transmembrane transporter activity / photoreceptor outer segment / Peptide ligand-binding receptors / GTPase activator activity / G protein-coupled receptor binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / 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 / 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 / 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 / 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 / blood coagulation / 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 / regulation of cell population proliferation / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / nuclear membrane / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / periplasmic space / learning or memory / protein stabilization / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / Golgi apparatus / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol 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 Å | |||||||||||||||||||||
![]() | Zhan, Y. / Peng, S. / Zhang, H. | |||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy. 著者: Shuman Peng / Yuting Zhan / Dongqi Zhang / Lu Ren / Anqi Chen / Zhou-Feng Chen / Haitao Zhang / ![]() ![]() 要旨: Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, ...Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe, β-Ala, Phe, Nle] Bn (6-14), in complex with G heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus. | |||||||||||||||||||||
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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 | ![]() | 235.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 176.9 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 754.6 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 765.2 KB | 表示 | |
XML形式データ | ![]() | 36.5 KB | 表示 | |
CIF形式データ | ![]() | 56.5 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 BCD
#2: タンパク質 | 分子量: 41194.844 Da / 分子数: 1 / 変異: R183Q, Q209L / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P50148 |
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#3: タンパク質 | 分子量: 41398.137 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: P62873 |
#4: タンパク質 | 分子量: 9242.612 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 |
-タンパク質 / 抗体 / タンパク質・ペプチド , 3種, 3分子 AHE
#1: タンパク質 | 分子量: 99534.102 Da / 分子数: 1 / 変異: E198A, N199A, K265A, I157A / 由来タイプ: 組換発現 詳細: The fusion protein of Maltodextrin-binding, protein,HiBit expression tag and Gastrin-releasing peptide receptor 由来: (組換発現) ![]() ![]() ![]() 遺伝子: malE, GRW33_05015, GRPR 発現宿主: ![]() ![]() 参照: UniProt: A0A6D0N546, UniProt: P30550 |
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#5: 抗体 | 分子量: 32785.582 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() |
#6: タンパク質・ペプチド | 分子量: 1118.307 Da / 分子数: 1 / 由来タイプ: 合成 / 由来: (合成) synthetic construct (人工物) |
-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: Peptide Receptor in complex with the agonist Bombesin (6-14) [D-Phe6, beta-Ala11, Phe13, Nle14] and Gq heterotrimers and ScFv16 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: 7.5 |
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: ![]() |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 64 e/Å2 フィルム・検出器のモデル: GATAN K2 BASE (4k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.18.2_3874: / 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: 3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1380329 / 対称性のタイプ: POINT |