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データを開く
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基本情報
| 登録情報 | データベース: EMDB / ID: EMD-13454 | ||||||||||||
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| タイトル | Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound to agonist NDP-alpha-MSH at 2.86 A resolution. | ||||||||||||
マップデータ | |||||||||||||
試料 |
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キーワード | GPCR / MELANOCORTIN-4 RECEPTOR / MELANOCORTIN RECEPTORS / SETMELANOTIDE / NDP-ALPHA-MSH / ALPHA-18 MSH / ANTAGONISM / AGONISM / APPETITE REGULATION / ANTI-OBESITY TREATMENT / SIGNALING PROTEIN | ||||||||||||
| 機能・相同性 | 機能・相同性情報regulation of eating behavior / response to melanocyte-stimulating hormone / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / melanocyte-stimulating hormone receptor activity / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 ...regulation of eating behavior / response to melanocyte-stimulating hormone / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / melanocyte-stimulating hormone receptor activity / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / melanocortin receptor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G beta:gamma signalling through BTK / Thromboxane signalling through TP receptor / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G alpha (s) signalling events / Ca2+ pathway / G alpha (12/13) signalling events / Extra-nuclear estrogen signaling / G alpha (q) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / GPER1 signaling / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (i) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / ADP signalling through P2Y purinoceptor 1 / neuropeptide binding / 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 / positive regulation of bone resorption / G alpha (z) signalling events / feeding behavior / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / 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) / insulin secretion / regulation of metabolic process / photoreceptor outer segment membrane / response to food / spectrin binding / alkylglycerophosphoethanolamine phosphodiesterase activity / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / cardiac muscle cell apoptotic process / photoreceptor inner segment / cellular response to glucagon stimulus / Transcriptional and post-translational regulation of MITF-M expression and activity / regulation of insulin secretion / Peptide ligand-binding receptors / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / response to insulin / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / platelet aggregation / cognition / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of smell / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding 類似検索 - 分子機能 | ||||||||||||
| 生物種 | Homo sapiens (ヒト) / synthetic construct (人工物) / ![]() ![]() ![]() | ||||||||||||
| 手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.86 Å | ||||||||||||
データ登録者 | Heyder NA / Schmidt A / Kleinau G / Hilal T / Scheerer P | ||||||||||||
| 資金援助 | ドイツ, 3件
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引用 | ジャーナル: Cell Res / 年: 2021タイトル: Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide. 著者: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / ...著者: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / Thorsten Mielke / Annette G Beck-Sickinger / Peter W Hildebrand / Christian M T Spahn / Daniel Hilger / Magdalena Schacherl / Heike Biebermann / Tarek Hilal / Peter Kühnen / Brian K Kobilka / Patrick Scheerer / ![]() 要旨: The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of ...The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs. | ||||||||||||
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構造の表示
| ムービー |
ムービービューア |
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| 構造ビューア | EMマップ: SurfView Molmil Jmol/JSmol |
| 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_13454.map.gz | 4.9 MB | EMDBマップデータ形式 | |
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| ヘッダ (付随情報) | emd-13454-v30.xml emd-13454.xml | 23.5 KB 23.5 KB | 表示 表示 | EMDBヘッダ |
| FSC (解像度算出) | emd_13454_fsc.xml | 9.7 KB | 表示 | FSCデータファイル |
| 画像 | emd_13454.png | 67 KB | ||
| Filedesc metadata | emd-13454.cif.gz | 7.9 KB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-13454 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13454 | HTTPS FTP |
-検証レポート
| 文書・要旨 | emd_13454_validation.pdf.gz | 384 KB | 表示 | EMDB検証レポート |
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| 文書・詳細版 | emd_13454_full_validation.pdf.gz | 383.7 KB | 表示 | |
| XML形式データ | emd_13454_validation.xml.gz | 11 KB | 表示 | |
| CIF形式データ | emd_13454_validation.cif.gz | 14.5 KB | 表示 | |
| アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13454 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13454 | HTTPS FTP |
-関連構造データ
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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 |
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マップ
| ファイル | ダウンロード / ファイル: emd_13454.map.gz / 形式: CCP4 / 大きさ: 83.7 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 0.832 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
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試料の構成要素
-全体 : Ternary complex of the NDP-alpha-MSH activated melanocortin 4 rec...
| 全体 | 名称: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 receptor (MC4R) Gs protein complex stabilized by nanobody 35 |
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| 要素 |
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-超分子 #1: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 rec...
| 超分子 | 名称: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 receptor (MC4R) Gs protein complex stabilized by nanobody 35 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 144.6 kDa/nm |
-分子 #1: Melanocortin receptor 4
| 分子 | 名称: Melanocortin receptor 4 / 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: 38.69852 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI ...文字列: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI MTVKRVGIII SCIWAACTVS GILFIIYSDS SAVIICLITM FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GT GAIRQGA NMKGAITLTI LIGVFVVCWA PFFLHLIFYI SCPQNPYCVC FMSHFNLYLI LIMCNSIIDP LIYALRSQEL RKT FKEIIC CYPLGGLCDL SSRYLEVLFQ UniProtKB: Melanocortin receptor 4 |
-分子 #2: NDP-alpha-MSH (other names Afamelanotide; Scenesse)
| 分子 | 名称: NDP-alpha-MSH (other names Afamelanotide; Scenesse) / 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: synthetic construct (人工物) |
| 分子量 | 理論値: 1.632863 KDa |
| 配列 | 文字列: (ACE)SYS(NLE)EH(DPN)RW GKPV(NH2) |
-分子 #3: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...
| 分子 | 名称: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short 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: Homo sapiens (ヒト) |
| 分子量 | 理論値: 44.32616 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI ...文字列: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI DVIKQADYVP SDQDLLRCRV LTSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVASSS YN MVIREDN QTNRLQEALN LFKSIWNNRW LRTISVILFL NKQDLLAEKV LAGKSKIEDY FPEFARYTTP EDATPEPGED PRV TRAKYF IRDEFLRIST ASGDGRHYCY PHFTCAVDTE NIRRVFNDCR DIIQRMHLRQ YELL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short |
-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: 37.728152 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 配列 | 文字列: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...文字列: GPGSSGSELD 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 WDSFLKIWN 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: 7.861143 KDa |
| 組換発現 | 生物種: Trichoplusia ni (イラクサキンウワバ) |
| 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 #6: Camelid antibody VHH fragment - nanobody 35
| 分子 | 名称: Camelid antibody VHH fragment - nanobody 35 / 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: 14.71432 KDa |
| 組換発現 | 生物種: ![]() |
| 配列 | 文字列: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHH |
-分子 #7: CALCIUM ION
| 分子 | 名称: CALCIUM ION / タイプ: ligand / ID: 7 / コピー数: 1 / 式: CA |
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| 分子量 | 理論値: 40.078 Da |
-分子 #8: water
| 分子 | 名称: water / タイプ: ligand / ID: 8 / コピー数: 115 / 式: HOH |
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| 分子量 | 理論値: 18.015 Da |
| Chemical component information | ![]() ChemComp-HOH: |
-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 |
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試料調製
| 濃度 | 1.2 mg/mL | ||||||||||||||||||||||||
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| 緩衝液 | pH: 7.5 構成要素:
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| グリッド | モデル: UltrAuFoil R1.2/1.3 / 材質: GOLD / 前処理 - タイプ: GLOW DISCHARGE | ||||||||||||||||||||||||
| 凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 283 K / 装置: FEI VITROBOT MARK IV |
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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: FEI FALCON III (4k x 4k) 検出モード: COUNTING / 撮影したグリッド数: 1 / 実像数: 5618 / 平均露光時間: 40.78 sec. / 平均電子線量: 40.0 e/Å2 |
| 電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
| 電子光学系 | C2レンズ絞り径: 50.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 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): 0.8 µm / 倍率(公称値): 96000 |
| 試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
| 実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
ムービー
コントローラー
万見について



キーワード
Homo sapiens (ヒト)
データ登録者
ドイツ, 3件
引用
UCSF Chimera





























Z (Sec.)
Y (Row.)
X (Col.)
























解析



