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基本情報
登録情報 | ![]() | |||||||||||||||||||||
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タイトル | Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide and Gq heterotrimers | |||||||||||||||||||||
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![]() | GPCR / Gastrin Releasing Peptide Receptor / MEMBRANE PROTEIN | |||||||||||||||||||||
機能・相同性 | ![]() response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / entrainment of circadian clock ...response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / psychomotor behavior / neuropeptide binding / G protein-coupled peptide receptor activity / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / motor behavior / phototransduction, visible light / social behavior / carbohydrate transmembrane transporter activity / photoreceptor outer segment / neuropeptide signaling pathway / postsynaptic cytosol / response to prostaglandin E / enzyme regulator activity / GTPase activator activity / Peptide ligand-binding receptors / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / G protein-coupled receptor binding / 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-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / blood coagulation / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / regulation of cell population proliferation / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / nuclear membrane / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / G alpha (q) signalling events / Ras protein signal transduction / learning or memory / periplasmic space / Extra-nuclear estrogen signaling / cell population proliferation / protein stabilization / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / GTP binding / protein-containing complex binding / Golgi apparatus / signal transduction / extracellular exosome / metal ion binding / membrane 類似検索 - 分子機能 | |||||||||||||||||||||
生物種 | ![]() | |||||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.0 Å | |||||||||||||||||||||
![]() | Zhan Y / Peng S | |||||||||||||||||||||
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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-検証レポート
文書・要旨 | ![]() | 370.4 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 370 KB | 表示 | |
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-関連構造データ
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.014 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
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試料の構成要素
-全体 : Human Gastrin Releasing Peptide Receptor in complex with the agon...
全体 | 名称: Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide and Gq heterotrimers and ScFv16 |
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要素 |
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-超分子 #1: Human Gastrin Releasing Peptide Receptor in complex with the agon...
超分子 | 名称: Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide and Gq heterotrimers and ScFv16 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: ![]() |
-分子 #1: Maltodextrin-binding protein,Gastrin-releasing peptide receptor
分子 | 名称: Maltodextrin-binding protein,Gastrin-releasing peptide receptor タイプ: protein_or_peptide / ID: 1 詳細: Fusion protein of Maltodextrin-binding protein, HiBit expression tag and Gastrin-releasing peptide receptor コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 99.534102 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFP QVAATGDGPD IIFWAHDRFG GYAQSGLLAE ITPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN K DLLPNPPK ...文字列: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFP QVAATGDGPD IIFWAHDRFG GYAQSGLLAE ITPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN K DLLPNPPK TWEEIPALDK ELKAKGKSAL MFNLQEPYFT WPLIAADGGY AFKYAAGKYD IKDVGVDNAG AKAGLTFLVD LI KNKHMNA DTDYSIAEAA FNKGETAMTI NGPWAWSNID TSAVNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEF LENYLL TDEGLEAVNK DKPLGAVALK SYEEELAKDP RIAATMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDE ALKDA QTHSADLPVN DDWSHPGILY VIPAVYGVII LIGLIGNITL IKIFCTVKSM RNVPNLFISS LALGDLLLLI TCAPV DASR YLADRWLFGR IGCKLIPFIQ LTSVGVSVFT LTALSADRYK AIVRPMDIQA SHALMKACLK AAFIWIISML LAIPEA VFS DLHPFHEEST NQTFISCAPY PHSNELHPKI HSMASFLVFY VIPLSIISVY YYFIAKNLIQ SAYNLPVEGN IHVKKQI ES RKRLAKTVLV FVGLFAFCWL PNHVIYLYRS YHYSEVDTSM LHFVTSICAR LLAFTNSCVN PFALYLLSKS FRKQFNTQ L LCCQGSSGGG GSGGGGSSGF TLEDFVGDWE QTAAYNLDQV LEQGGVSSLL QNLAVSVTPI QRIVRSGENA LKIDIHVII PYEGLSADQM AQIEEVFKVV YPVDDHHFKV ILPYGTLVID GVTPNMLNYF GRPYEGIAVF DGKKITVTGT LWNGNKIIDE RLITPDGSM LFRVTINS UniProtKB: Maltodextrin-binding protein, Gastrin-releasing peptide receptor |
-分子 #2: Gastrin Releasing Peptide PRGNHWAVGHLM(NH2)
分子 | 名称: Gastrin Releasing Peptide PRGNHWAVGHLM(NH2) / 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: ![]() |
分子量 | 理論値: 1.375604 KDa |
配列 | 文字列: PRGNHWAVGH LM(NH2) |
-分子 #3: Guanine nucleotide-binding protein G(q) subunit alpha
分子 | 名称: Guanine nucleotide-binding protein G(q) subunit alpha 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: ![]() |
分子量 | 理論値: 41.194844 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA RRELKLLLLG TGESGKSTFI KQMRIIHGSG YSDEDKRGFT KLVYQNIFTA MQAMIRAMD TLKIPYKYEH NKAHAQLVRE VDVEKVSAFE NPYVDAIKSL WNDPGIQECY DRRREYQLSD STKYYLNDLD R VADPAYLP ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA RRELKLLLLG TGESGKSTFI KQMRIIHGSG YSDEDKRGFT KLVYQNIFTA MQAMIRAMD TLKIPYKYEH NKAHAQLVRE VDVEKVSAFE NPYVDAIKSL WNDPGIQECY DRRREYQLSD STKYYLNDLD R VADPAYLP TQQDVLRVQV PTTGIIEYPF DLQSVIFRMV DVGGLRSERR KWIHCFENVT SIMFLVALSE YDQVLVESDN EN RMEESKA LFRTIITYPW FQNSSVILFL NKKDLLEEKI MYSHLVDYFP EYDGPQRDAQ AAREFILKMF VDLNPDSDKI IYS HFTCAT DTENIRFVFA AVKDTILQLN LKEYNLV UniProtKB: Guanine nucleotide-binding protein G(q) subunit alpha |
-分子 #4: 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: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 41.398137 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD ...文字列: MHHHHHHHHH HGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD NQIVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HE SDINAIC FFPNGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAG VLAGHD NRVSCLGVTD DGMAVATGSW DSFLKIWNGS SGGGGSGGGG SSGVSGWRLF KKIS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #5: 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: 5 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 9.242612 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #6: ScFv16
分子 | 名称: ScFv16 / 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: ![]() |
分子量 | 理論値: 32.785582 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG ...文字列: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELKE NLYFQGHHHH HHHHHH |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K2 BASE (4k x 4k) 平均電子線量: 64.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: OTHER / 撮影モード: BRIGHT FIELD |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |