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基本情報
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タイトル | Macimorelin bound growth hormone secretagogue receptor in complex with Gq | ||||||||||||
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![]() | Macimorelin / growth hormone secretagogue receptor / GHSR / GPCR / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | ||||||||||||
機能・相同性 | ![]() growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / ghrelin secretion / response to follicle-stimulating hormone ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / ghrelin secretion / response to follicle-stimulating hormone / positive regulation of appetite / growth hormone secretion / negative regulation of norepinephrine secretion / positive regulation of eating behavior / positive regulation of small intestine smooth muscle contraction / negative regulation of macrophage apoptotic process / adult feeding behavior / negative regulation of appetite / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / response to growth hormone / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of postsynapse organization / positive regulation of vascular endothelial cell proliferation / response to food / negative regulation of interleukin-1 beta production / positive regulation of fatty acid metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / cellular response to insulin-like growth factor stimulus / regulation of synapse assembly / response to L-glutamate / positive regulation of sprouting angiogenesis / response to dexamethasone / negative regulation of interleukin-6 production / peptide hormone binding / decidualization / negative regulation of tumor necrosis factor production / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / response to hormone / hormone-mediated signaling pathway / insulin-like growth factor receptor signaling pathway / Peptide ligand-binding receptors / synaptic membrane / electron transport chain / G protein-coupled receptor activity / Schaffer collateral - CA1 synapse / negative regulation of inflammatory response / Olfactory Signaling Pathway / Activation of the phototransduction cascade / cellular response to insulin stimulus / 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 / 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 / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / response to estradiol / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / cellular response to lipopolysaccharide / GTPase binding / retina development in camera-type eye / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / spermatogenesis / G alpha (q) signalling events 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: 2.63 Å | ||||||||||||
![]() | Wang R / Sun J / Liu H / Guo S / Zhang Y / Hu W / Wang J / Zhuang Y / Jiang Y / Xie X ...Wang R / Sun J / Liu H / Guo S / Zhang Y / Hu W / Wang J / Zhuang Y / Jiang Y / Xie X / Xu H / Wang Y | ||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor. 著者: Ruo-Lan Wang / Jun Sun / Heng Liu / Shi-Meng Guo / Yu Zhang / Wen Hu / Jiang Wang / Hong Liu / You-Wen Zhuang / Yi Jiang / Xin Xie / H Eric Xu / Yue Wang / ![]() 要旨: The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition ...The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition is essential for developing therapeutic interventions. In this study, we investigated the molecular recognition mechanisms of two clinically approved drugs: Macimorelin (used for diagnosing adult growth hormone deficiency) and Anamorelin (approved in Japan for cancer cachexia). Using high-resolution cryo-electron microscopy, we determined the structures of GHSR bound to Macimorelin and Anamorelin in complex with G proteins at resolutions of 2.63 Å and 2.52 Å, respectively. We revealed that both drugs occupied a bifurcated binding pocket divided by a conserved salt bridge between E124 and R283. Through systematic mutagenesis and functional studies, we identified the key residues underlying the higher binding affinity of Anamorelin compared to Macimorelin. In addition, structural comparison of GHSR in complex with different G protein subtypes elucidated the mechanisms driving G protein selectivity. Our results provide crucial insights into GHSR-drug interactions and offer valuable guidance for designing more selective and potent GHSR agonists. | ||||||||||||
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-EMDBアーカイブ
マップデータ | ![]() | 59.7 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 21.8 KB 21.8 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 8.4 KB | 表示 | ![]() |
画像 | ![]() | 48.2 KB | ||
Filedesc metadata | ![]() | 7.1 KB | ||
その他 | ![]() ![]() | 59.4 MB 59.4 MB | ||
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 | ![]() 9v2nMC ![]() 9uy3C M: このマップから作成された原子モデル 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
EMDBのページ | ![]() ![]() |
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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: 0.73 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: #1
ファイル | emd_64734_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: #2
ファイル | emd_64734_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 |
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試料の構成要素
-全体 : Macimorelin bound growth hormone secretagogue receptor in complex...
全体 | 名称: Macimorelin bound growth hormone secretagogue receptor in complex with Gq |
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要素 |
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-超分子 #1: Macimorelin bound growth hormone secretagogue receptor in complex...
超分子 | 名称: Macimorelin bound growth hormone secretagogue receptor in complex with Gq タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Engineered G-alpha-q subunit
分子 | 名称: Engineered G-alpha-q subunit / 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: ![]() |
分子量 | 理論値: 41.855578 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY ...文字列: MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY IPTQQDVLRT RVKTSGIFET KFQVDKVNFH MFDVGAQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL ND FKSIWNN RWLRTISVIL FLNKQDLLAE KVLAGKSKIE DYFPEFARYT TPEDATPEPG EDPRVTRAKY FIRKEFVDIS TAS GDGRHI CYPHFTCSVD TENARRIFND CKDIILQMNL REYNLV |
-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: ![]() |
分子量 | 理論値: 40.226992 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...文字列: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: 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: 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: 7.861143 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #4: NB35
分子 | 名称: NB35 / 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: 15.343019 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A |
-分子 #5: Soluble cytochrome b562,Growth hormone secretagogue receptor type...
分子 | 名称: Soluble cytochrome b562,Growth hormone secretagogue receptor type 1,growth hormone secretagogue receptor 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: 76.149734 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MKTIIALSYI FCLVFAHHHH HHHHHHPSRL EEELRRRLTE PADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKL EDKSPDSPEM KDFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLMW NATPSEEPGF N LTLADLDW ...文字列: MKTIIALSYI FCLVFAHHHH HHHHHHPSRL EEELRRRLTE PADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKL EDKSPDSPEM KDFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAYIQKYLMW NATPSEEPGF N LTLADLDW DASPGNDSLG DELLQLFPAP LLAGVTATCV ALFVVGIAGN LLTMLVVSRF RELRTTTNLY LSSMAFSDLL IF LCMPLDL VRLWQYRPWN FGDLLCKLFQ FVSESCTYAT VLTITALSVE RYFAICFPLR AKVVVTKGRV KLVIFVIWAV AFC SAGPIF VLVGVEHENG TDPWDTNECR PTEFAVRSGL LTVMVWVSSI FFFLPVFCLT VLYSLIGRKL WRRRRGDAVV GASL RDQNH KQTVKMLAVV VFAFILCWLP FHVGRYLFSK SFEPGSLEIA QISQYCNLVS FVLFYLSAAI NPILYNIMSK KYRVA VFRL LGFEPFSQRK LSTLKDESSR AWTESSINTG SAGSVFTLED FVGDWEQTAA YNLDQVLEQG GVSSLLQNLA VSVTPI QRI VRSGENALKI DIHVIIPYEG LSADQMAQIE EVFKVVYPVD DHHFKVILPY GTLVIDGVTP NMLNYFGRPY EGIAVFD GK KITVTGTLWN GNKIIDERLI TPDGSMLFRV TINS UniProtKB: Soluble cytochrome b562, Growth hormone secretagogue receptor type 1 |
-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: 32.561281 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: LLVNQSHQGF NKEHTSKMVS AIVLYVLLAA AAHSAFAVQL VESGGGLVQP GGSRKLSCSA SGFAFSSFGM HWVRQAPEKG LEWVAYISS GSGTIYYADT VKGRFTISRD DPKNTLFLQM TSLRSEDTAM YYCVRSIYYY GSSPFDFWGQ GTTLTVSAGG G GSGGGGSG ...文字列: LLVNQSHQGF NKEHTSKMVS AIVLYVLLAA AAHSAFAVQL VESGGGLVQP GGSRKLSCSA SGFAFSSFGM HWVRQAPEKG LEWVAYISS GSGTIYYADT VKGRFTISRD DPKNTLFLQM TSLRSEDTAM YYCVRSIYYY GSSPFDFWGQ GTTLTVSAGG G GSGGGGSG GGGSADIVMT QATSSVPVTP GESVSISCRS SKSLLHSNGN TYLYWFLQRP GQSPQLLIYR MSNLASGVPD RF SGSGSGT AFTLTISRLE AEDVGVYYCM QHLEYPLTFG AGTKLELVDE NLYFQGASHH HHHHHH |
-分子 #7: Macimorelin
分子 | 名称: Macimorelin / タイプ: ligand / ID: 7 / コピー数: 1 / 式: A1EQV |
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分子量 | 理論値: 474.555 Da |
-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: 7.3 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TALOS ARCTICA |
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撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 平均電子線量: 50.0 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: OTHER / 最大 デフォーカス(公称値): 2.0 µm / 最小 デフォーカス(公称値): 1.0 µm |
実験機器 | ![]() モデル: Talos Arctica / 画像提供: FEI Company |